CIPROFOL VS PROPOFOL

30 Dec 20225 Jan 2023THE ANESTHESIA CONSULTANT Leave a comment

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Physician anesthesiologist at Stanford at Associated Anesthesiologists Medical Group

Richard Novak, MD is a Stanford physician board certified in anesthesiology and internal medicine.Dr. Novak is an Adjunct Clinical Professor in the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University, the Medical Director at Waverley Surgery Center in Palo Alto, California, and a member of the Associated Anesthesiologists Medical Group in Palo Alto, California.
emailrjnov@yahoo.com

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Ciprofol is a new intravenous (IV) anesthetic agent which is undergoing early clinical trials in China, and may become a significant tool in our anesthesia armamentarium if and when the drug is approved by the Food and Drug Administration (FDA) in the United States. Ciprofol has a chemical structure similar to propofol. Because of its rapid onset and rapid offset profile, propofol is currently the most used IV anesthetic drug in the world. Propofol is used for surgical anesthesia, procedural sedation, and intensive care unit (ICU) sedation. Propofol was FDA-approved in the United States in 1986 and is now off patent. Generic propofol is inexpensive, averaging about $2.27 for a 20 ml vial. Limitations of propofol include (a) respiratory depression, such that it can only be used by physicians who are expert in airway management (e.g. anesthesiologists, CRNAs, and emergency room doctors); (b) hemodynamic depression in some elderly or sick patients; (c) pain on injection; and (d) the propofol infusion syndrome (PIS) which can lead to hyperkalemia and cardiac arrest in ICU patients after prolonged exposure to propofol infusions.

The chemical formula of ciprofol is similar to propofol, but with single R-configured diastereoisomers.

Ciprofol is about 5 times more potent than propofol. Like propofol, ciprofol is formulated in a lipid emulsion with a drug concentration of 10 mg/mL. Let’s review the published literature on ciprofol to date. All of the following studies were done in China:

Phase 1 trials (small groups of subjects are given a single dose of the drug, and are observed and tested for a period of time to confirm safety):

Teng et al. (2021) conducted a phase I trial which demonstrated that a ciprofol dosing regimen of 0.4-0.9 mg/kg was well-tolerated and exhibited rapid onset and recovery properties. Peak plasma concentration occurred 2 minutes after injection, and all subjects recovered fully after ciprofol administration, with the shortest time being 9.2 minutes in the 0.4 mg/kg group.

Hu et al. (2021) also conducted a phase I trial in which subjects received continuous ciprofol or propofol infusions for up to 12 hours. The safety and tolerability of both drugs were comparable.

Phase II trials (performed on larger groups, e.g. 50–300 patients, to evaluate whether the drug has any biological activity or effect):

Teng et al. (2021) conducted a study on 1000 patients, which showed that ciprofol 0.4-0.5 mg/kg induced equivalent sedation/anesthesia to propofol 2.0 mg/kg during colonoscopy, and had a similar safety profile without producing serious adverse effects. No apnea was observed in any patients in the ciprofol group, but 5 patients in the propofol 2.0 mg/kg group experienced apnea. The incidence of injection pain was higher in the propofol group than in the ciprofol group (55% vs 6.8%). There were no significant dose-dependent changes in blood pressure in either the ciprofol or propofol groups.

Liu et al. (2021) conducted a phase II trial which involved 36 ICU patients who were on mechanical ventilation. A remifentanil infusion of 0.02–0.15 μg·kg⁻¹·min⁻¹ plus either ciprofol or propofol were used for analgesia and sedation. The ciprofol loading dose was 0.1–0.2 mg/kg with a maintenance infusion rate of 0.3 mg/kg/h. The propofol loading was at 0.5–1.0 mg/kg, with a maintenance infusion rate of 1.5 mg/kg/h. The tolerability, sedation characteristics, and adverse events such as hypotension were comparable between both groups. The authors concluded that “ciprofol is comparable to propofol with good tolerance and efficacy for sedation of Chinese intensive care unit patients undergoing mechanical ventilation in the present study setting.”

The propofol infusion syndrome (PIS) is a potentially lethal syndrome that occurs due to prolonged infusion described in adults and pediatric ICU patients who are on mechanical ventilation. To date, published studies have not administered multi-day infusions of ciprofol to mechanically ventilated ICU patients to determine whether there is anything similar to PIS with ciprofol.

Wu et al. (2022) published a single-center trial on 92 patients titled “Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy.” Fentanyl (50 μg) was given to all patient 2 minutes before the intravenous administration of either 0.3 mg/kg of ciprofol or 1.2 mg/kg of propofol, followed by a remifentanil infusion in both groups. Top-up doses of one-third to one-fourth of the initial dose of ciprofol or propofol were repeated at 2-minute intervals as needed. The two drugs were comparable. The authors concluded that “ciprofol-remifentanil was non-inferior to propofol-remifentanil with regard to successful sedation for flexible bronchoscopy.” Systolic, diastolic, and mean blood pressures declined significantly less in the ciprofol-remifentanil group (p < 0.05). There was no difference in respiratory depression between the two groups, and the only statistical difference in adverse effects was a decrease in pain on injection for ciprofol over propofol (p=.001).

Chen et al. (2022) compared ciprofol and propofol in 120 women for the induction of anesthesia in gynecologic surgery. Intravenous midazolam (0.03 mg/kg) and sufentanil (0.3 μg/kg) were administered initially, followed by ciprofol (0.4 mg/kg) or propofol (2 mg/kg). After the loss of consciousness, rocuronium (0.6 mg/kg) was administered and endotracheal intubation was performed. Within the initial 10 minutes following study drug administration, blood pressure declined significantly less in the ciprofol group than in the propofol group. The authors concluded that “ciprofol was associated with slightly less pronounced effects on the cardiovascular system.” The incidence of injection pain was higher in the propofol group than in the ciprofol group (58% vs 16%, p < 0.001).

Chen et al. (2022) studied adverse reactions of ciprofol and propofol in 96 patients for gastroenteroscopy. Neither ciprofol nor propofol caused statistically significant differences in vital signs. The authors concluded that “in painless gastroenteroscopy, compared with propofol, ciprofol is equally safe and effective for patients.”

Lan et al. (2022) randomized 150 patients to ciprofol or propofol for hysteroscopy. All patients received intravenous sufentanil 0.1 μg/kg IV initially. Ciprofol patients then received an induction dose of 0.4 mg/kg and a maintenance dosage of 1.0 mg/kg/h. Propofol patients received an induction dose of 2.0 mg/kg and a maintenance dosage of 5.0 mg/kg/h. After the sedative administration, the systolic, diastolic, and mean pressures all dropped significantly lower in the propofol group than in the ciprofol group. During the procedure, 2/75 ciprofol patients vs 17/75 propofol patients required an airway intervention such as a chin-lift or jaw-thrust maneuver (p< 0.05). The authors concluded that “the lower level of respiratory depression seen with ciprofol makes this drug more suitable and safer than propofol for hysteroscopic procedures.”

Phase III trials (randomized controlled multicenter trials on larger patient groups, aimed at determining how effective the drug is in comparison with the current “gold standard” treatment, i.e. propofol):

Li et al. (2022) conducted a phase III study at ten teaching hospitals, comparing ciprofol and propofol for deep sedation for colonoscopy or gastroscopy. A total of 289 patients were studied. Each patient received 50 μg fentanyl 1 minute before the intravenous infusion of either ciprofol (0.4 mg/kg) or propofol (1.5 mg/kg). Up to five top-up doses of 1/2 the initial dose were given upon signs of inadequate sedation, and repeated at 2-minute intervals as required. The mean time for a patient to become fully alert after the procedure was 3.3 minutes in the ciprofol group vs. 2.0 minutes for the propofol group (P < 0.001). The time to discharge was 7.4 minutes for the ciprofol group vs. 6.0 minutes for the propofol group (P < 0.001). Nine patients (6.3%) in the ciprofol group and 15 patients (10.3%) in the propofol group had respiratory events (respiratory depression, apnea, or hypoxemia), all of which were mild or moderate in severity. The authors concluded that “at a dose of 0.4 mg/kg for deep sedation, ciprofol was non-inferior to 1.5 mg/kg propofol in the success rate of gastroscopy and colonoscopy and exhibited a good safety profile.”

Wang et al. (2022) published a multi-center, double-blind phase III trial in which 186 surgery patients were randomly assigned to either ciprofol 0.4 mg/kg or propofol 2.0 mg/kg for the induction of general anesthesia. Ciprofol was “non-inferior” to propofol. Once again, the incidence of injection pain was significantly lower in the ciprofol patients compared to the propofol patients (6.8% vs. 20.5%, p < 0.05).

MY TAKE: WILL CIPROFOL BE A SUCCESSFUL ADDITION TO OUR IV ANESTHESIA DRUG ARSENAL?

It depends.

If ciprofol and propofol were cost-equivalent, ciprofol would gain some market share, and might prove to be a superior drug to propofol. However, when and if it is FDA-approved in the United States, ciprofol will cost significantly more than propofol because ciprofol will be on patent. Hospitals and surgery centers will be reluctant to pay more for the drug unless there are proven advantages. Ciprofol appears to have significantly less pain on injection when compared to propofol, but pain on injection with propofol is not a major issue. Pain on injection does not lead to any long term adverse outcomes, and the pain can be blocked by injecting IV lidocaine immediately prior the initial dose of IV propofol.
The data that ciprofol leads to less blood pressure decreases than propofol shows only a mild difference—too small an advantage to mandate replacing propofol with ciprofol for that reason alone.
So far there are no data to confirm or deny that there is any equivalent to propofol infusion syndrome with ciprofol. If there is no prolonged infusion syndrome, then ciprofol may find a market for ICU sedation of mechanically ventilated patients.
Overall, I believe ciprofol must promise a lack of respiratory depression if the new drug is to capture any of propofol’s market share for procedural sedation/surgical anesthesia. The most bothersome issue with propofol is the risk of respiratory depression, which requires an anesthesia professional or airway expert administer the drug. If a patient is oversedated with propofol, that patient may stop breathing or have upper airway obstructed breathing, which can lead to hypoxia, cardiac arrest, and anoxic brain damage. The FDA warnings for propofol include:

For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN Injectable Emulsion should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.

In the Li study above, 6.3% of the ciprofol patients had mild to moderate respiratory adverse events when sedated for GI endoscopy. While the 6.3% rate is lower than the 10.3% rate for the propofol patients, the non-zero incidence of respiratory events with ciprofol in this one study points to an anesthesia professional still needing to be present if ciprofol is administered for endoscopy.

In the Lan study above, during IV sedation only 2/75 ciprofol patients, compared with 17/75 propofol patients, required airway intervention such as with a chin-lift or a jaw-thrust maneuver during hysteroscopy (p< 0.05). This lower incidence of required airway intervention is encouraging, but the incidence is still not zero, and we’ll need more data to document the respiratory risks of ciprofol.

If ciprofol sedation is found to NOT produce any significant respiratory depression, apnea, or upper airway obstruction (therefore less risk of hypoxia and anoxic brain damage), this would be a profound advance over propofol. Then ciprofol could be administered for procedural sedation, e.g. for gastroenteroscopy, without an anesthesia airway expert attending to the patient. There is insufficient studies to date to know whether this will be true or not.

My guess? After all the data is in, ciprofol will cause a non-zero incidence of respiratory depression, and therefore a non-zero risk of hypoxia and anoxic brain damage, so an anesthesia airway expert will be necessary to administer the drug. The advantage of ciprofol’s lower but non-zero incidence of required airway intervention will not be a major advance in the hands of anesthesia professionals. The higher cost of ciprofol will preclude the decision of hospitals and surgery centers to switch to ciprofol until the new drug is off patent.

We’ll have to wait for more data on ciprofol, but don’t be surprised if propofol remains on top of the intravenous sedative/hypnotic anesthesia drug pedestal after the studies are concluded.

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REMIMAZOLAM: NEW WONDER ANESTHETIC DRUG OR MEDICAL WHITE ELEPHANT?

24 Mar 202224 Mar 2022THE ANESTHESIA CONSULTANT 9 Comments

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THE ANESTHESIA CONSULTANT

Physician anesthesiologist at Stanford at Associated Anesthesiologists Medical Group

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In July 2020 the Food and Drug Administration (FDA) approved the intravenous benzodiazepine remimazolam (Byfavo, Acacia Pharma) for use in sedation for procedures of 30 minutes or less. Will anyone utilize this new drug, or is it an expensive addition to our arsenal with few significant advantages over current agents?

Remimazolam differs from midazolam (Versed), the current most commonly used IV benzodiazepine, in that remimazolam is rapidly converted to an inactive metabolite by tissue esterases, resulting in an ultra-short onset/offset profile. Remimazolam is marketed as a powder which must be reconstituted into a liquid within its vial prior to administration.

For use in procedural sedation, remimazolam will not replace Versed, but rather will aim to replace propofol. The proposed advantages of remimazolam over propofol include:

Remimazolam can be completely reversed by the benzodiazepine antagonist flumazenil (Romazicon) whereas there is no reversal agent or antagonist for propofol. The only way to end the sedative effects of propofol is for an anesthesia professional to support the airway, breathing, and circulation of the patient until the drug effects of propofol wear off in time.
Remimazolam has minimal cardiac or respiratory depression. Sicker ASA III and IV patients maintain their breathing and circulation status while under remimazolam sedation.
There is no accumulative effect of remimazolam over time. Its elimination by an esterase does not slow during lengthy administration of remimazolam, as in the prolonged sedation of an intensive care unit (ICU) patient on a ventilator.
There is no burning sensation upon injecting remimazolam into a patient’s intravenous line as there is with propofol.
A non-anesthesia-professional can administer remimazolam, whereas an anesthesia professional/airway expert must administer and monitor propofol administration.

Are these advantages important? Items 1 – 5 are discussed as follows:

Non-anesthesiologists can reverse the effects of remimazolam with flumazenil if they overdose a patient, but this advantage is less important for anesthesia professionals. Anesthesiologists can manage the airway of a patient over-sedated with a benzodiazepine without need to administer a reversal agent. I’ve never administered a dose of flumazenil in my entire career, nor have most of my anesthesia colleagues.
Propofol has cardiac and respiratory depression, but in most cases these effects are minimal. Per the PDR (Physician’s Digital Reference), patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g. septic patients) are more susceptible to hypotension. When an anesthesiologist is present these risks are routinely managed.
For a long operating room anesthesia case (e.g. of 8 – 10 hours duration), there is no clinically significant accumulation of propofol in the bloodstream. Propofol Infusion Syndrome (PRIS), which can be potentially fatal, is a risk with prolonged propofol sedation in the ICU (See ICU Sedation below).
The burning sensation upon injecting propofol can be blunted by intravenous lidocaine. A 2016 meta-analysis showed that both lidocaine pretreatment and mixing lidocaine with the propofol were effective in reducing pain on propofol injection. In addition, a preanesthetic dose of Versed prevents a patient from remembering any burning sensation from a propofol injection that follows.
The most important advantage of remimazolam is that non-anesthesiologists can safely administer remimazolam. Propofol administration requires an experienced clinician, e.g. either an anesthesiologist, a certified registered nurse anesthetist (CRNA), or an emergency medicine physician. Per the American Society of Anesthesiologists: “The practitioner administering propofol for sedation/anesthesia should, at a minimum, have the education and training to identify and manage the airway and cardiovascular changes which occur in a patient who enters a state of general anesthesia.”

The disadvantages of remimazolam compared to propofol include:

Expense. The cost of a 20 ml (200 mg) vial of propofol is $9.20. The cost of a 20 mg vial of powdered remimazolam is $41.67.
Remimazolam is sold as a powder and must be reconstituted into a liquid before it can be injected intravenously.

Remimazolam is currently approved as an anesthesia drug in Japan and South Korea, for intensive care unit sedation in Belgium, but only for procedural sedation in the United States, China, and Europe. In total, there are four possible applications for remimazolam. Let’s examine the pros and cons of using remimazolam in these four applications:

Preoperative sedation. Since midazolam (Versed) was approved in 1982, a standard anesthesia practice has included a 2 mg dose of Versed prior to surgery to calm a patient’s anxiety. In the 1980s my anesthesia chairman at Stanford received a letter from a postoperative patient in which she complained of being awake and very anxious in the operating room prior to the anesthetic for her breast cancer surgery. Our chairman lectured to us, “Do you know many patients are nervous prior to their anesthesia and surgery? Every one of them. We have an excellent drug for relieving preoperative anxiety, and that drug is Versed. Use it! Give your patient a dose of Versed before they enter the operating room. There are few significant side effects of one dose of Versed. Use it!” Will remimazolam replace Versed for this application? No. There is no advantage of the new, shorter acting, more expensive remimazolam over Versed for preoperative sedation.
Sedation for short procedures. This is the FDA-approved application for remimazolam in the United States. An example procedure would be a colonoscopy. Will remimazolam be widely used for colonoscopies in the near future? No, I doubt it. The cost increase is the main disadvantage. See the typical drug acquisition costs for three alternative sedation recipes for colonoscopy below:

$18.40 for 400 mg of propofol; or

$5.17 for fentanyl+Versed ($4.35 dollars for 6 mg of Versed plus $0.82 for 200 micrograms of fentanyl); or

$41.67 for 20 mg of remimazolam.

The increased cost per case is $23.27 for remimazolam over propofol.

The increased cost per case is $36.50 for remimazolam over fentanyl+Versed.

If a busy endoscopy center does 100 colonoscopies cases per week, the cost increase is $2327 per week for remimazolam over propofol, or $3650 per week for remimazolam over fentanyl+Versed. These are a prohibitive cost increases with no clear added benefits. The only way remimazolam could result in cheaper sedation costs would be if a healthcare system was looking to eliminating the cost of paying for an anesthesia provider for these procedures. The pairing of remimazolam+gastroenterologist sedation rather than propofol+anesthesiologist sedation could afford significant cost savings for a healthcare system.

3. Total intravenous anesthesia (TIVA). TIVA could include a continuous infusion of the ultra-short-acting narcotic remifentanil plus a continuous infusion of the ultra-short-acting remimazolam. An alleged advantage of this technique could be the fast offset time of these two TIVA anesthetic agents. I doubt this technique will gain market share. It’s far easier to turn on the knob of a sevoflurane vaporizer than to load and manage two TIVA-syringe pumps. As well, the added expense of a prolonged infusion of remimazolam will be prohibitive.

4. ICU sedation. Remimazolam has the advantage of ongoing first-degree elimination, meaning that no matter how long the drug is infused, it will always have reliable elimination by esterase and will not accumulate in the plasma. Prolonged ICU sedation with propofol can lead to the Propofol Infusion Syndrome (PRIS). PRIS occurs predominantly in patients receiving high doses of propofol for a prolonged period. Risk factors for the development of PRIS include a critical illness such as sepsis, head trauma, use of vasopressors, and carbohydrate depletion (liver disease, starvation, or malnutrition). PRIS commonly presents as a high anion gap metabolic acidosis, with rhabdomyolysis, hyperkalemia, acute kidney injury, elevated liver enzymes, and decreased cardiac output. Because of the risk of PRIS, the duration of propofol infusion administration should not exceed 48 hours and the administered dose should not be higher than 4 mg/kg/hour.

This potential advantage of remimazolam over propofol will be offset by the increased expense of hours or days of remimazolam utilization in an ICU sedation situation. ICU sedation with fentanyl and older benzodiazepines such as Ativan will have the advantage of a lower cost.

In the hands of an anesthesiologist, propofol is an elegant and almost ideal intravenous sedative, with the advantages of rapid onset, rapid offset, inexpensive generic pricing, minimal cardiovascular/respiratory depression, and lack of nausea. Propofol administration does carry the risks of upper airway obstruction, hypoventilation, and low oxygen saturation, but when an anesthesiologist is present these risks are minimal.

If a healthcare organization doesn’t want to employ an anesthesiologist or a CRNA for a case which requires procedural sedation, then remimazolam may be an excellent sedative choice. Will gastroenterologists prefer to sedate patients with remimazolam plus fentanyl without an anesthesiologist? Or will they prefer to have an anesthesiologist present to administer propofol? Expect gastroenterologists to prefer the latter, because they are not only off-loading the task of sedating the patient, they are also off-loading the risks of managing the patient’s medical co-morbidities, which can be significant if a patient has lung disease, cardiac disease, morbid obesity, or obstructive sleep apnea.

The remimazolam story suggests one of my favorite anecdotes: A former Stanford Chairman of Anesthesiology and friend of mine who left the university in 2006 to become a pharmaceutical company executive, first at Novartis and then at AstraZeneca. Ten years ago, when I asked him what new anesthesia drugs were in the pipeline, he answered, “None, and there probably will be very few new ones. The drugs you have now are inexpensive generic drugs, and they work very well. The research and development costs to bring a new anesthetic drug to market are prohibitively expensive, and unless that new drug is markedly better, it will not push the inexpensive generic drugs out of use.”

Remimazolam will capture a very small market in the United States. Until remimazolam becomes an inexpensive generic drug, I see it as a medical white elephant rather than a wonderful anesthetic advance.