How does propofol induce anesthesia. What are the potential side effects of propofol. Why is propofol use restricted to trained professionals. Can propofol mimic natural sleep. How does propofol affect sleep deprivation in ICU patients.

The Fundamentals of Propofol: A Powerful Anesthetic Agent

Propofol is a widely used intravenous anesthetic agent that has gained significant attention in recent years, particularly following the tragic death of pop icon Michael Jackson. To understand this potent drug, we must first explore its primary functions and applications in modern medicine.

Propofol serves two main purposes in clinical settings:

1. Inducing anesthesia in surgical patients
2. Providing sedation for patients in Intensive Care Units (ICUs)

Dr. Avery Tung, an associate professor of anesthesia and critical care at the Medical Center, explains that propofol has largely replaced pentothal as the most common induction agent for anesthesia. This shift is due to propofol’s fewer side effects and improved patient experience upon waking.

How does propofol work to induce anesthesia?

Propofol acts on the central nervous system by enhancing the effects of GABA (gamma-aminobutyric acid), the primary inhibitory neurotransmitter in the brain. This action leads to a rapid onset of sedation and unconsciousness, making it ideal for initiating general anesthesia in surgical procedures.

Potential Side Effects and Risks Associated with Propofol Use

While propofol offers several advantages over older anesthetic agents, it is not without risks. Understanding these potential side effects is crucial for both medical professionals and patients.

The main side effects of propofol include:

• Decreased blood pressure
• Respiratory depression or cessation
• Pain at the injection site

These side effects highlight the importance of proper administration and monitoring by trained professionals. The potential for respiratory depression, in particular, underscores the need for careful oversight during propofol use.

Are there any long-term effects of propofol use?

While propofol is generally considered safe for short-term use, prolonged or repeated exposure may lead to complications. Some studies have suggested potential impacts on cognitive function and memory, particularly in elderly patients. However, more research is needed to fully understand the long-term effects of propofol use.

Restricted Use: Why Propofol Administration Requires Specialized Training

Given the potent nature of propofol and its potential side effects, its use is strictly regulated in medical settings. Dr. Tung emphasizes that propofol should only be administered by individuals trained in general anesthesia, typically anesthesiologists.

In ICU settings, propofol use is further restricted to intubated, mechanically ventilated patients. This limitation is in place to ensure patient safety and proper monitoring of vital functions.

Why is specialized training crucial for propofol administration?

Dr. Tung explains that propofol can be deceptively easy to use due to its rapid onset and quick recovery time. However, this ease of use can lead to dangerous situations if not properly managed. The risk of patients slipping from sedation into general anesthesia, coupled with potential blood pressure and breathing difficulties, necessitates specialized resuscitation measures that only trained professionals can provide.

Propofol in the ICU: Balancing Comfort and Safety

While propofol’s primary use is in surgical anesthesia, it also plays a crucial role in ICU settings. Understanding its application in this context helps illuminate the drug’s versatility and importance in modern medicine.

Why is propofol used in non-surgical cases in the ICU?

Propofol serves several purposes for ICU patients:

• Alleviating discomfort, pain, and anxiety in mechanically ventilated patients
• Managing agitation to ensure patient and staff safety
• Facilitating tolerance of mechanical ventilation
• Providing deep sedation when necessary

It’s important to note that not all ICU patients require sedation, and the depth of sedation varies based on individual patient needs and conditions.

The Sleep Conundrum: Propofol’s Impact on Sleep Deprivation in ICU Patients

One of the most intriguing aspects of propofol is its potential relationship to sleep. Dr. Tung’s research has focused on this connection, particularly in the context of sleep deprivation in ICU settings.

Why is sleep deprivation a significant issue in the ICU?

Sleep deprivation has been a recognized problem in ICUs since the 1980s. Several factors contribute to this issue:

• Constant lighting
• Persistent noise levels
• Frequent nurse checks (often hourly)
• Disruption of normal circadian rhythms
• Potential pain and anxiety experienced by patients

While the direct impact of sleep deprivation on ICU outcomes remains unclear due to the difficulty in establishing control groups, it undoubtedly complicates patient care and recovery.

Unraveling the Propofol-Sleep Connection: Groundbreaking Research Findings

Dr. Tung’s research has shed light on the fascinating relationship between propofol sedation and natural sleep. His studies have explored whether propofol can mimic the restorative effects of natural sleep, potentially offering a solution to the sleep deprivation problem in ICU settings.

Can propofol sedation substitute for natural sleep?

Dr. Tung’s initial study involved sedating rats with propofol during their normal sleep period and comparing their behavior to rats allowed to sleep naturally. The results were striking: rats sedated with propofol showed no more signs of sleep deprivation than those that experienced natural sleep.

This finding led to two possible conclusions:

1. Propofol prevents the accumulation of “sleep debt”
2. Propofol, like natural sleep, helps discharge existing sleep debt

How did further research expand on these findings?

To further investigate the propofol-sleep connection, Dr. Tung conducted a second experiment focusing on recovery from sleep deprivation. This study aimed to determine whether propofol sedation could replicate the “rebound” effect typically seen after sleep deprivation.

In this experiment, rats were sleep-deprived for 24 hours using a rotating platform method. Following this deprivation period, some rats were allowed to sleep naturally, while others received propofol sedation. The researchers then observed the rats’ recovery patterns to compare the effects of natural sleep versus propofol-induced sedation.

Implications of Propofol Research: Potential Applications and Future Directions

The findings from Dr. Tung’s research have significant implications for both clinical practice and our understanding of sleep physiology. By demonstrating that propofol sedation may mimic some of the restorative effects of natural sleep, this research opens up new avenues for managing sleep deprivation in ICU settings and beyond.

How might these findings impact ICU care?

If further research confirms that propofol can indeed substitute for natural sleep in terms of its restorative effects, it could revolutionize ICU care protocols. Potential applications include:

• Developing targeted sedation strategies to combat sleep deprivation
• Improving patient outcomes by ensuring adequate “sleep-like” rest
• Reducing the negative impacts of prolonged ICU stays on patients’ sleep-wake cycles

However, it’s crucial to note that more research is needed to fully understand the long-term implications of using propofol as a sleep substitute and to establish safe and effective protocols for its use in this context.

What questions remain unanswered in propofol-sleep research?

While Dr. Tung’s studies have provided valuable insights, several questions remain to be explored:

1. How does propofol-induced sedation compare to natural sleep in terms of cognitive restoration and memory consolidation?
2. Are there differences in the long-term effects of propofol sedation versus natural sleep on overall health and recovery?
3. Can propofol be safely used as a sleep aid outside of ICU settings, and if so, under what circumstances?
4. How does propofol interact with the brain’s natural sleep-wake cycle and circadian rhythms?

Answering these questions will require further research and collaboration between experts in anesthesiology, sleep medicine, and neuroscience.

The Ethical Considerations of Propofol Use: Balancing Benefits and Risks

As with any powerful medical intervention, the use of propofol raises important ethical considerations. The potential benefits of its sleep-mimicking effects must be carefully weighed against the risks associated with its use, particularly in non-surgical contexts.

What ethical concerns surround propofol use outside of surgical settings?

Several ethical issues arise when considering the broader application of propofol:

• The risk of misuse or abuse, as highlighted by high-profile cases like Michael Jackson’s death
• The potential for dependency or addiction in patients exposed to long-term propofol use
• The balance between patient comfort and safety in ICU settings
• The implications of using a powerful anesthetic as a substitute for natural sleep

Addressing these ethical concerns will be crucial as research into propofol’s sleep-related effects continues to evolve.

How can medical professionals ensure responsible propofol use?

To promote ethical and safe use of propofol, healthcare providers and institutions should consider the following measures:

1. Strict adherence to guidelines restricting propofol administration to trained anesthesia professionals
2. Ongoing education and training for medical staff on the risks and proper use of propofol
3. Implementation of robust monitoring protocols for patients receiving propofol sedation
4. Development of clear policies regarding the use of propofol for sleep-related purposes in ICU settings
5. Continued research into the long-term effects and potential alternatives to propofol sedation

By prioritizing these measures, the medical community can work to harness the potential benefits of propofol while minimizing its associated risks.

The Future of Propofol Research: Exploring New Frontiers in Anesthesia and Sleep Medicine

As our understanding of propofol’s effects on the brain and body continues to grow, new avenues for research and potential applications are emerging. The intersection of anesthesia and sleep medicine represents a particularly promising area for future investigation.

What are some potential future directions for propofol research?

Several exciting areas of study are likely to shape the future of propofol research:

• Investigation of propofol’s effects on specific sleep stages and their associated cognitive functions
• Development of targeted propofol delivery systems to mimic natural sleep patterns more closely
• Exploration of propofol’s potential in treating chronic sleep disorders
• Study of the long-term neurological impacts of repeated propofol exposure
• Research into combinations of propofol with other sedatives or sleep-promoting agents

These research directions could lead to significant advancements in both anesthesia practices and sleep medicine.

How might propofol research impact our broader understanding of consciousness and sleep?

The study of propofol’s effects on the brain offers a unique window into the nature of consciousness and the mechanisms underlying sleep. By comparing the brain activity patterns during propofol-induced sedation with those observed during natural sleep, researchers may gain new insights into:

1. The neural correlates of consciousness
2. The role of specific brain regions in regulating sleep and wakefulness
3. The relationship between sleep and memory consolidation
4. The impact of sedation on cognitive function and recovery

These insights could have far-reaching implications for our understanding of the human mind and the treatment of various neurological and sleep-related disorders.

As research into propofol and its effects on sleep continues to evolve, it’s clear that this powerful anesthetic agent has much more to teach us about the complexities of the human brain and the nature of consciousness itself. While its use must always be approached with caution and respect for its potent effects, propofol remains a fascinating subject of study with the potential to revolutionize our approach to both anesthesia and sleep medicine.

Propofol: A Dangerous Kind of Rest

The death of Michael Jackson made its expected transition from a celebration of his life and music to an uncomfortable public autopsy of how he died. More than a month after his death, the official coroner’s autopsy had yet to be officially released, but various media outlets sniffed out one particular drug that appears in the pop star’s toxicology report: the general anesthetic propofol.

Avery Tung, associate professor of anesthesia and critical care for the Medical Center, conducted an NIH-funded research project examining relationships between sleep and anesthesia, and published several papers and scientific abstracts looking at how propofol mimicked the effects of actual sleep. After Tung sat down with ABC News following Jackson’s death,  we spent a little more time with him discussing the anesthetic and his research.

First of all, what is propofol, and how often is it used?

Tung: Propofol is given intravenously to induce anesthesia in surgical patients and to provide sedation for patients in the Intensive Care Unit. It’s the most common induction agent of anesthesia in current use. It pretty much has replaced pentothal because it has fewer side effects and it makes people feel better when they wake up.

What side effects does propofol have?

It can cause a decrease in blood pressure, it can depress or even stop breathing, and it can cause pain on injection.

And because of those side effects, its use is restricted?

The package insert with the drug states that it should only be used by persons trained in the administration of general anesthesia, which in this hospital means an anesthesiologist. In the ICU, it is restricted only for use in intubated, mechanically ventilated patients.

Why restrict it to use under an anesthesiologist’s guidance?

Propofol can be deceptively easy to use. Because people recover so quickly, there’s a temptation to use it in places which aren’t safe. But it’s stronger than other drugs, and can clearly destabilize blood pressure and breathing, Users can easily slip over the line from sedation to general anesthesia, develop blood pressure or breathing difficulties, and need specialized resuscitation measures.

Why is it used in non-surgical cases in the intensive care unit?

For a number of reasons. Mechanically ventilated patients can be uncomfortable, or experience pain and anxiety. They might also be a danger to themselves and others due to agitation, or need help to tolerate the ventilator. Not everybody in the ICU needs sedation, and some need to be sedated fairly deeply so that they are only partially responsive to stimulation.

You chose to study the effects of propofol on sleep deprivation. Is sleep deprivation an issue in the ICU?

Sleep deprivation is a huge issue in the ICU, and has been documented since the 1980’s. Because of potential pain and anxiety, because the lights are always on, because there is noise always present and nurses are checking on patients on an hourly basis, there is really no quiet time. The circadian rhythms and light cycles that people are normally exposed to aren’t as present in an ICU setting either. No one knows whether sleep deprivation adversely affects outcomes in the ICU because there’s no way to set up a control for sleep, but many of the effects of sleep deprivation can clearly make care in the ICU more difficult.

Tell me about the first propofol and sleep study you published

The first thing we did was to sedate rats with propofol for the entire period they would normally be asleep…and see how they would behave afterward relative to how they behaved beforehand, compared to rats that were allowed to sleep naturally. What we found is that rats were no more sleep deprived, as measured by EEG criteria, after a period of propofol sedation, than rats that underwent naturally-occurring sleep.

We concluded that the need to sleep was not accumulating inside rats that received propofol and therefore either propofol was preventing their “sleep debt” from building up or propofol was, like sleep, helping rats to discharge it.

You tested this conclusion again using a different experiment. How did that one work?

In the second experiment, we sleep deprived a rat and looked at the recovery from sleep deprivation. Normally when a rat is sleep deprived, it shows a rebound increase, a transient increase in sleep for a while as they sort of discharge their sleep need or sleep debt.

(Rats in this study were deprived of sleep for 24 hours by being placed on a platform above a pan of water. Whenever rats begin to sleep, the platform rotates, forcing them to wake up and walk to avoid splashing down in the water)

So we then allowed rats to sleep naturally or gave them a period of sedation with propofol and looked to see how they recover. What we found is that recovery in rats given propofol occurred as quickly as recovery in rats allowed to sleep normally. We concluded that, at least in rats, subjects can discharge their sleep debt under propofol sedation to the same degree as they are able to do it using naturally occurring sleep.

But does that mean that propofol sedation is the same as sleep?

Propofol sedation is nothing at all like sleep. Sleep is reversible with external stimulation – if you shake somebody, they wake up. Propofol is obviously not like that. Sleep shows a characteristic pattern of EEG behavior, while propofol does not. (For instance, Tung explains, cyclical patterns of REM and nonREM sleep are not observed during propofol sedation, in rats or humans) Sleep, in general, preserves blood pressure and the ability to breathe and propofol does not. They are very different states.

All of your propofol research has been in rats, has there been any research done in humans along these lines?

No, there has not. It does appear that humans given propofol for prolonged periods do not appear to be sleep deprived when you turn off the drug. No data exist to support the specific use that has been alleged in the Michael Jackson case (using propofol as a treatment for insomnia),. Use to facilitate regular sleep is not at all safe. The benefit is way outstripped by the risk…if there is any benefit.

Nobody is advocating its use outside a hospital for patients that are not critically ill. That is outside the boundaries of currently accepted care.

Propofol: Expert Q&A

Propofol is a strong anesthetic that’s used for surgery, some medical exams, and for sedation for people on ventilators — never as a sleep aid. It’s given by IV and should only be administered by a medical professional trained in its use. It takes effect in a matter of seconds.

“It is very fast-acting and works by slowing brain wave activities, says John F. Dombrowski, MD, an anesthesiologist/pain specialist at the Washington Pain Center in Washington, D.C.

Dombrowski, who is a board member of the American Society of Anesthesiologists, talked with WebMD about propofol’s uses and abuses.

Does propofol have approved or off-label uses besides for surgical anesthesia?

No.”I know of no off-label use or need for propofol,” Dombrowski says. “It has a perfect place in the medical community, and that’s in a surgical suite or ambulatory care setting.”

Is it unusual for propofol to be used outside of a hospital setting?

“It’s only to be used in a medical setting,” Dombrowski says. “Outside of a hospital, it may be used in an ambulatory care center or a doctor’s office, but only if it’s administered by a trained professional, not by the doctor performing the procedure. You can’t do your operation properly and do sedation at the same time. You can’t serve two masters. That will lead to sloppy surgery or sloppy anesthesia care, and patients don’t deserve that.”

How dangerous is propofol?

Propofol is a potentially deadly drug in the wrong hands, and there is no room for error.

“It’s only designed for people trained to do advanced cardiac life support,” Dombrowski says. “It induces a deep level of sleep and sedation, and it can cause your blood pressure to go down and your breathing to stop. You can die. Patients have to be monitored beat by beat, minute by minute.”

Can any doctor administer propofol, or is it more controlled?

“There’s no DEA (Drug Enforcement Administration) licensing requirement, so the answer is no. It’s not controlled and any physician can use it,” Dombrowski says. “But I hope that physicians who are not trained to use it will have the insight to say, ‘This is out of my comfort zone. What business do I have using this? None. ‘”

Can people get addicted to propofol? Is there any prolonged or repeated use of propofol?

“The concern for addiction is always there, but while there is abuse potential among hospital personnel who have access to propofol, for the general public, that potential is just not there,” Dombrowski says. “It’s an access issue. The general public has no access.”

“As for repeated uses, only if you are getting multiple procedures done. But there’s no one out there saying, ‘Hey, I’m going to get another hernia repair’ just to get some propofol.”

After someone has been on propofol and “wakes up,” how would they feel? How different is it from sleep?

“You feel alert, unlike with [the anesthetic] pentothal, which left patients feeling really worn out and hungover,” Dombrowski says.”But while propofol induces sleep, it’s not a clean, clear sleep.”

Are there any statistics on propofol abuse?

“Abuse just doesn’t occur, and if there’s any abuse potential, it’s so small that it’s not enough to talk about,” Dombrowski says. “There’s no access to it, and there’s no reason someone would want it.”

Uses, Dosage, Side Effects, Interactions, Warning

DOSAGE AND ADMINISTRATION

Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 minutes to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

Shake well before use. Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised. Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

When administering DIPRIVAN by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing DIPRIVAN to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN.

For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN and/or opioids should be increased in order to provide adequate anesthesia.

Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN at rates higher than are clinically necessary. Generally, rates of 50 mcg/kg/min to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (e.g., sedatives, anesthetics, and opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

Induction Of General Anesthesia

Adult Patients

Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 mg/kg to 2.5 mg/kg of DIPRIVAN for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, DIPRIVAN should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other general anesthetics, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN.

Elderly, Debilitated, Or ASA-PS III Or IV Patients

It is important to be familiar and experienced with the intravenous use of DIPRIVAN before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 mg/kg to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

Pediatric Patients

Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 mg/kg to 3.5 mg/kg of DIPRIVAN for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients. As with other general anesthetics, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN. A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid to minimize pain on injection when administering DIPRIVAN to pediatric patients. Boluses of DIPRIVAN may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

Neurosurgical Patients

Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower boluses or infusions of DIPRIVAN for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 mg/kg to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Cardiac Anesthesia

DIPRIVAN has been well-studied in patients with coronary artery disease, but experience in patients with  hemodynamically significant valvular or congenital heart disease is limited. As with other general anesthetics and sedation drugs, DIPRIVAN in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

In addition, lower heart rates are observed during maintenance with DIPRIVAN, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

As with other anesthetic agents, DIPRIVAN reduces myocardial oxygen consumption. Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.

Morphine premedication (0. 15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN maintenance infusion rates and therapeutic blood concentrations when compared to nonnarcotic (lorazepam) premedication. The rate of DIPRIVAN administration should be determined based on the patient’s premedication and adjusted according to clinical responses.

A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 mg/kg to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when DIPRIVAN is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an opioid is used as the primary agent, DIPRIVAN maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of DIPRIVAN will reduce the opioid requirements (see Table 4). When DIPRIVAN is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

Table 4: Cardiac Anesthesia Techniques

Primary Agent	Rate	Secondary Agent/Rate (Following Induction with Primary Agent)
DIPRIVAN		OPIOIDa/0.05 mcg/kg/min to 0.075 mcg/kg/min (no bolus)
Preinduction Anxiolysis	25 mcg/kg/min
Induction	0.5 mg/kg to 1.5 mg/kg over 60 sec
Maintenance (Titrated to Clinical Response)	100 mcg/kg/min to 150 mcg/kg/min
OPIOIDb		DIPRIVAN /50 mcg/kg/min to 100 mcg/kg/min (no bolus)
Induction	25 mcg/kg to 50 mcg/kg
Maintenance	0.2 mcg/kg/min to 0.3 mcg/kg/min
aOPIOID is defined in terms of fentanyl equivalents, i. e., 1 mcg of fentanyl = 5 mcg of alfentanil (for bolus) = 10 mcg of alfentanil (for maintenance) or= 0.1 mcg of sufentanil bCare should be taken to ensure amnesia.

Maintenance Of General Anesthesia

DIPRIVAN has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

Adult Patients

In adults, anesthesia can be maintained by administering DIPRIVAN by infusion or intermittent IV bolus injection. The patient’s clinical response will determine the infusion rate or the amount and frequency of incremental injections.

Continuous Infusion

DIPRIVAN 100 mcg/kg/min to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery. Maintenance by infusion of DIPRIVAN should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period following the induction dose, higher rates of infusion are generally required (150 mcg/kg/min to 200 mcg/kg/min) for the first 10 minutes to 15 minutes. Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.

Generally, rates of 50 mcg/kg/min to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

Other drugs that cause CNS depression (e.g., sedatives, anesthetics, and opioids) can increase the CNS depression induced by propofol.

Intermittent Bolus

Increments of DIPRIVAN 25 mg (2. 5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

Pediatric Patients

DIPRIVAN administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

In general, for the pediatric population, maintenance by infusion of DIPRIVAN at a rate of 200 mcg/kg/min to 300 mcg/kg/min should immediately follow the induction dose. Following the first half-hour of maintenance, infusion rates of 125 mcg/kg/min to 150 mcg/kg/min are typically needed. DIPRIVAN should be titrated to achieve the desired clinical effect. Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients. (See Table 2 Clinical Trials. )

Monitored Anesthesia Care (MAC) Sedation

Adult Patients

When DIPRIVAN is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response. In most patients, the rates of DIPRIVAN administration will be in the range of 25 mcg/kg/min to 75 mcg/kg/min.

During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

Initiation Of MAC Sedation

For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be initiated by infusing DIPRIVAN at 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/h to 9 mg/kg/h) for a period of 3 minutes to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 minutes to 5 minutes and titrated to clinical responses. When DIPRIVAN is administered slowly over 3 minutes to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). The rate of administration should be over 3 minutes to 5 minutes and the dosage of DIPRIVAN should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

Maintenance Of MAC Sedation

For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require maintenance rates of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/h to 4.5 mg/kg/h) during the first 10 minutes to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to 25 mcg/kg/min to 50 mcg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN at rates higher than are clinically necessary.

If the intermittent bolus dose method is used, increments of DIPRIVAN 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS). The rate of administration and the dosage of DIPRIVAN should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

DIPRIVAN can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures. When DIPRIVAN sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN and may also result in a slower recovery profile (see DRUG INTERACTIONS).

ICU Sedation

(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures. )

Abrupt discontinuation of DIPRIVAN prior to weaning or for daily evaluation of sedation levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

Adult Patients

For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).

Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION). With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation. These higher rates of administration may increase the likelihood of patients developing hypotension. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

DIPRIVAN should be individualized according to the patient’s condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation). For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/h to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) or higher. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). Dosages of DIPRIVAN should be reduced in patients who have received large dosages of narcotics. The DIPRIVAN dosage requirement may also be reduced by adequate management of pain with analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see Summary Of Dosage Guidelines). Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation). Bolus administration of 10 mg or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

Summary Of Dosage Guidelines

Dosages and rates of administration in the following table should be individualized and titrated to clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older. Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older.

For complete dosage information, see DOSAGE AND ADMINISTRATION.

INDICATION	DOSAGE AND ADMINISTRATION
Induction of General Anesthesia:	Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2 mg/kg to 2. 5    mg/kg). Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds until induction onset (1 mg/kg to 1.5    mg/kg). Cardiac Anesthesia: 20 mg every 10 seconds until induction onset (0.5 mg/kg to 1.5 mg/kg). Neurosurgical Patients: 20 mg every 10 seconds until induction onset (1 mg/kg to 2 mg/kg). Pediatric Patients – healthy, from 3 years to 16 years of age: 2.5    mg/kg to 3.5 mg/kg administered over 20 seconds to 30 seconds. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics).
Maintenance of General Anesthesia:	Infusion Healthy Adults Less Than 55 Years of Age: 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/h to 12 mg/kg/h). Elderly, Debilitated, ASA-PS III or IV Patients: 50 mcg/kg/min to 100 mcg/kg/min (3 mg/kg/h to 6 mg/kg/h). Cardiac Anesthesia: Most patients require: Primary DIPRIVAN with Secondary Opioid – 100 mcg/kg/min to 150 mcg/kg/min. Low-Dose DIPRIVAN with Primary Opioid – 50 mcg/kg/min to 100 mcg/kg/min. (see DOSAGE AND ADMINISTRATION, Table 4). Neurosurgical Patients: 100 mcg/kg/min to 200 mcg/kg/min (6 mg/kg/h to 12 mg/kg/h). Pediatric Patients – healthy, from 2 months of age to 16 years of age: 125 mcg/kg/min to 300 mcg/kg/min (7.5 mg/kg/h to 18 mg/kg/h). Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased. (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics).
Maintenance of General Anesthesia:	Intermittent Bolus Healthy Adults Less Than 55 Years of Age: Increments of 20 mg to 50 mg as needed.
Initiation of MAC Sedation:	Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Most patients require an infusion of 100 mcg/kg/min to 150 mcg/kg/min (6 mg/kg/h to 9 mg/kg/h) for 3 minutes to 5 minutes or a slow injection of 0.5 mg/kg over 3 minutes to 5 minutes followed immediately by a maintenance infusion. Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require dosages similar to healthy adults. Rapid boluses are to be avoided (see WARNINGS).
Maintenance of MAC Sedation:	Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique. Most patients require an infusion of 25 mcg/kg/min to 75 mcg/kg/min (1.5 mg/kg/h to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg. In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients: Most patients require 80% of the usual adult dose. A rapid (single or repeated) bolus dose should not be used (see WARNINGS).
Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated
	Adult Patients – Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0. 3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 mcg/kg/min to 10 mcg/kg/min (0.3 mg/kg/h to 0.6 mg/kg/h) over 5 minutes to 10 minutes may be used until desired clinical effect is achieved. Maintenance rates of 5 mcg/kg/min to 50 mcg/kg/min (0.3 mg/kg/h to 3 mg/kg/h) or higher may be required. Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation. The tubing and any unused DIPRIVAN drug product should be discarded after 12 hours because DIPRIVAN contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS and DOSAGE AND ADMINISTRATION).

Administration With Lidocaine

If lidocaine is to be administered to minimize pain on injection of DIPRIVAN, it is recommended that it be administered prior to DIPRIVAN administration or that it be added to DIPRIVAN immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

Compatibility And Stability

DIPRIVAN should not be mixed with other therapeutic agents prior to administration.

Dilution Prior To Administration

DIPRIVAN is provided as a ready-to-use formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

Administration With Other Fluids

Compatibility of DIPRIVAN with the coadministration of blood/serum/plasma has not been established (see WARNINGS). When administered using a y-type infusion set, DIPRIVAN has been shown to be compatible with the following intravenous fluids.

• 5% Dextrose Injection, USP
• Lactated Ringers Injection, USP
• Lactated Ringers and 5% Dextrose Injection
• 5% Dextrose and 0. 45% Sodium Chloride Injection, USP
• 5% Dextrose and 0.2% Sodium Chloride Injection, USP

Handling Procedures

General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Clinical experience with the use of in-line filters and DIPRIVAN during anesthesia or ICU/MAC sedation is limited. DIPRIVAN should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN and/or cause the breakdown of the emulsion. Filters should be used with caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

Do not use if there is evidence of separation of the phases of the emulsion.

Rare cases of self-administration of DIPRIVAN by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

Strict aseptic technique must always be maintained during handling. DIPRIVAN is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination. However, DIPRIVAN can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling DIPRIVAN was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons. DIPRIVAN vials are never to be accessed more than once or used on more than one person.

Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

Guidelines For Aseptic Technique For General Anesthesia/MAC Sedation

DIPRIVAN must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. DIPRIVAN should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN from vials, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

DIPRIVAN must be prepared for single-patient use only. Any unused DIPRIVAN drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner. The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN.

Guidelines For Aseptic Technique For ICU Sedation

DIPRIVAN must be prepared for single-patient use only. Strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN. As with other lipid emulsions, the number of IV line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused DIPRIVAN drug product must be discarded after 12 hours.

If DIPRIVAN is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing DIPRIVAN from a vial, a sterile vent spike should be used. The syringe should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened. DIPRIVAN should be discarded and administration lines changed after 12 hours.

HOW SUPPLIED

DIPRIVAN (propofol) Injectable Emulsion, USP Vials

Product No.	NDC No.	Strength
260910	63323-269-10	100 mg per 10 mL (10 mg per mL)	10 mL ready-to-use singlepatient infusion vial in packages of ten.
260929	63323-269-29	200 mg per 20 mL (10 mg per mL)	20 mL ready-to-use singlepatient infusion vial in packages of ten.
260950	63323-269-50	500 mg per 50 mL (10 mg per mL)	50 mL ready-to-use singlepatient infusion vial in packages of twenty.
260965	63323-269-65	1,000 mg per 100 mL (10 mg per mL)	100 mL ready-to-use single-patient infusion vial in packages of ten.

Propofol undergoes oxidative degradation, in the presence of oxygen, and is therefore packaged under nitrogen to eliminate this degradation path.

Store between 4° to 25°C (40° to 77°F). Do not freeze. Shake well before use.

Manufactured for: Lake Zurich, IL 60047. Revised: Jan 2020

What Is the New Development?

Abstract

Propofol is a short-acting intravenous anesthetic agent suitable for induction and maintenance of general anesthesia as well as for procedural and intensive care unit sedation. As such it has become an unparalleled anesthetic agent of choice in many institutional and office practices. However, in addition to its idealistic properties as an anesthetic agent, there is accumulating evidence suggesting its potential for abuse. Clinical and experimental evidence has revealed that not only does propofol have the potential to be abused, but also that addiction to propofol shows a high mortality rate. Based on this evidence, different researchers have shown interest in determining the probability of propofol to be an addictive agent by comparing it with other drugs of abuse and depicting a functional similitude that involves the mesocorticolimbic pathway of addiction. In light of this, the Drug Enforcement Agency and the American Society of Anesthesiologists have put forth certain safety recommendations for the use of propofol. Despite this, the abuse potential of propofol has been challenged at different levels and therefore the preeminent focus will be to further validate the linkage from medicinal and occasional use of propofol to its addiction, as well as to explore the cellular and molecular targets involved in establishing this linkage, so as to curb the harm arising out of it. This review incorporates the clinical and biomolecular evidence supporting the abuse potential of propofol and brings forth the promising targets and the foreseeable mechanism causing the propofol addiction phenotypes, which can be called upon for future developments in this field.

Keywords: propofol, abuse potential, GABA_A receptor, glycine receptor, fospropofol

1. Introduction

Propofol is a sedative hypnotic used widely in different healthcare settings such as operating rooms and offices. Though it is currently not classified as a controlled substance, there is increasing evidence that propofol has abuse potential and presents risks of addiction that should warrant a re-consideration of this regulation. In this review, we will discuss the evidence supporting increasing incidence of propofol abuse and the comparability of its actions with other substances of addiction such as alcohol and nicotine, in particular on the mesolimbic reward system.

2. Clinical Properties of Propofol

Propofol is a fast-acting intravenous hypnotic medication extensively used for induction and maintenance of general anesthesia, monitored anesthesia care (MAC), and for conscious sedation in the setting of intensive care units (ICUs) of hospitals. Additional uses for propofol include refractory agitated delirium and as an antiemetic in patients with end-stage diseases or patients undergoing chemotherapy [1]. Propofol may also be used for the treatment of intractable status epilepticus, delirium tremens, and status asthmaticus and has anti-inflammatory properties that may be useful in sepsis and traumatic brain injury. Propofol has several advantages over other sedatives due to its rapid onset, short duration of action, faster metabolism, and rapid clearance. It has minimal or no residual side effects and hence it is widely used for anesthesia and sedation.

Propofol’s principal mechanism of action is to enhance chloride current at the gamma-aminobutyric acid type A (GABA_A) receptor on the post-synaptic membrane of neurons. This mechanism is also responsible for its antiepileptic and anxiolytic effects [2]. Glycine receptors and ligand-gated chloride channels, which mediate neuronal inhibition at the spinal level, have also shown sensitivity to propofol [3].

3. Abuse Potential of Propofol

Although the vast majority of reported abuse of propofol has been by medical professionals, risk of its abuse in the general population has been highlighted in numerous case reports and case studies worldwide time and again [4,5]. Propofol’s incrimination in pop music superstar Michael Jackson’s death in 2009 resulted in giving more momentum to the awareness regarding propofol addiction. However, abuse of propofol has been widely reported since 1992. Propofol induces psychotropic effects similar to other drugs of addiction and clinical research involving healthy volunteers showed that sub-anesthetic doses of propofol induced feelings of “drunk”, “dizzy”, “elated”, and “high”, along with decreased feelings of “in control of thoughts” and “in control of body” [6]. A random-choice trial was conducted in healthy volunteers in which subjects were asked to choose between propofol and placebo (Intralipid, a soy-based lipid emulsion) after blind bolus injections of either propofol or placebo. This trial resulted in a statistically significant difference in choosing propofol over placebo than would be expected by chance. Moreover, propofol was chosen for its pleasant subjective effects whereas the placebo was chosen for unpleasant effects associated with propofol administration such as dizziness, confusion, or weakness. These trials show that propofol, as with other drugs of abuse, can induce pleasant feelings that can increase its risk for recreational use as well as addiction.

Studies have shown an increase in the reporting of drug abuse that can be attributed to propofol. An analysis of 22 cases of propofol addiction in healthcare providers treated at a large addiction center between 1990 and 2010 was done by Earley et al. [7] who found that there was 25% increase in admissions reporting propofol use, in each semi-decade, in the treatment groups. Anesthesia providers constituted a majority of the cases reported, and all providers had relatively easy access to propofol. Self-reported reasons for propofol use included insomnia, anxiety, and seeking euphoria. Noteworthy is the possibility of second-hand exposure to propofol through air in the operating room which produces sensitization to the reinforcing effects of propofol, thereby possibly driving towards addiction with repeated exposure; however, the evidence to prove it is very miniscule [8,9]. In an e-mail survey of 126 academic anesthesiology training programs in the US in 2006, observed incidence of propofol abuse over the past 10 years was 10 per 10,000 anesthesia providers with a high incidence of mortality (28%) among those abusing propofol [10]. This represents an increased incidence of reported propofol abuse compared to a prior survey from 1990 to 1997 which had a calculated 10-year incidence rate of 0.02%. The survey also found that there was a significant association between error in propofol accounting and episodes of abuse. In a retrospective survey of substance abuse in anesthetists in Australia and New Zealand from 2004 to 2013, propofol was the most commonly abused substance (41%) [11]. Propofol was inculpated in all eight cases that resulted in death, in which three were identified as suicides and five as overdose, highlighting the significant mortality associated with propofol abuse. These studies demonstrate a trend towards an increasing incidence of propofol abuse and the significant mortality associated with its abuse.

4. Status of Propofol as a Controlled Drug

The Drug Enforcement Agency (DEA) issued its final rule effective 5 November 2009 placing fospropofol, a prodrug of propofol, into schedule IV of the Controlled Substances Act [12]. Fospropofol’s increased bioavailability when taken orally versus propofol’s negligible oral bioavailability increases its risk for abuse [13]. Thus, the regulatory controls and criminal sanctions of schedule IV are applicable to the manufacture, distribution, dispensing, importation, and exportation of fospropofol and products containing fospropofol. Accordingly, fospropofol will remain readily available for use by responsible clinicians in urgent and emergent situations but will require that it be reasonably stored in a restricted and secure environment with access limited to qualified clinicians. On the other hand, though the DEA proposed its inclusion into schedule IV of the Controlled Substances Act in October 2010, propofol, which is the active metabolite of fospropofol, is not yet on the list of controlled substances [14]. This proposal has been supported by the American Society of Anesthesiologist (ASA), which unequivocally maintains that propofol should be used in a medical setting by professionals trained in provision of general anesthesia and with proper supervision by a physician trained in anesthesia and qualified to provide rescue, should it be required [15]. American Association of Nurse Anesthetists (AANA) recommends that propofol be placed in a secure environment only accessible by the professionals identified in a medication management policy thereby taking measures towards decreasing drug diversion [16].

Others have argued against classifying propofol as a controlled substance. Some properties of propofol including pain on injection and rapid onset have been cited against its potential for abuse. Due to propofol’s advantages over other sedatives, it has become an indispensable tool in modern anesthesiology practices. Impeding access to such a ubiquitous medication may unnecessarily add administrative load and cost to implement controls and delay access during critical emergencies. Therefore, any such action should be viewed with respect to these forthcoming challenges.

5. Molecular and Cellular Mechanisms of Propofol Addiction

The abuse potential of propofol that is observed clinically can be very well substantiated through animal studies [17]. Gatch et al. [18] showed that propofol produces a discriminable stimulus similar to known drugs of abuse. There is a growing evidence showing that propofol can be self-administered [17,19] and induces a conditioned place preference [20,21], which are the classic methods to evaluate the abuse potential of drugs. This implies that propofol, as with other drugs of abuse, is subject to reinforcing effects. The abuse potential of propofol has been further studied by various labs at the neurocircuitry, molecular and cellular levels and is discussed in this section.

The mesocorticolimbic pathway is the key component of reward circuitry involved in addiction to drugs [22,23,24]. Evidence shows that different drugs of abuse exert their action on different primary target proteins to bring about behavioral and physiological rewarding effects of the drug. However, with acute and eventually chronic use, the drugs which have a potential for abuse converge on a common pathway of addiction which involves, most commonly, the mesolimbic dopaminergic output of Ventral Tegmental Area (VTA) to the Nucleus Accumbens (NAc) [25]. Most drugs of abuse encode for a novel or unexpected reward and result in large but transient increases in NAc dopamine levels via phasic firing of VTA dopamine neurons. Similar increase also results from specific cues related to the drug. The thus increased dopamine mediates the motivation to procure the reinforcer via low affinity dopamine D1 receptors acting on the direct striatal pathway of reward as well as sustain this motivation via high affinity dopamine D2 receptors inhibiting the indirect striatal pathway of aversion. In due course, synaptic and neuronal plasticity develops and results in craving for the drug even with lower increases in dopamine levels observed in chronic drug abusers [26].

The NAc is closely connected to emotion-regulating areas of the brain which are modulated by dopamine to motivate goal-directed behaviors in response to novel stimuli. Dopamine influences the forming of these responses via downstream transcription and protein synthesis, the products of which are targets of study for drugs of addiction. Animal model studies have been instrumental in studying these drug-induced changes. Several studies have been performed to compare the effect of propofol with other drugs of abuse, on the mesolimbic reward circuit. A study by Pain et al. [27] used micro dialysis to measure dopamine levels in the NAc of rats after different doses of propofol. Propofol was injected intraperitoneally at the following doses: 0, 9, 60, 100 mg/kg. Dopamine concentrations were decreased at 9 mg/kg dose but were largely increased by approximately 90% in both sub-anesthetic dose of 60 mg/kg and at anesthetic dose of 100 mg/kg, with anesthetic doses resulting in prolonged increase in dopamine levels. However, their results cannot differentiate between the increased release of dopamine or inhibition of dopamine re-uptake that resulted in increased dopamine levels.

A study by Wang et al. [19] focused on the significance of extracellular signal-regulated kinase (ERK) signal transduction pathways in NAc during propofol self-administration. The study showed that there is significantly increased expression of phosphorylated EKR (p-ERK) in the NAc in rats maintained on propofol, and pretreatment with SCh33390 (a D1 receptor antagonist) inhibited propofol self-administration and diminished the expression of p-ERK in the NAc. Intra NAc injection of ERK kinase inhibitor, U0126 (4 µg/side), attenuated the propofol self-administration. These results were consistent with several previous studies showing an increased p-ERK expression in the NAc following cocaine and ethanol self-administration [28]. Thus, the study hypothesized that ERK signal transduction pathways coupled with D1 dopamine receptors in the NAc is critical for downstream regulation of DA signal transmission in the NAc, mediating the increased self-administration and rewarding effects observed with propofol.

The Finkel-Biskins-Jinkins murine osteosarcoma viral oncogene homolog B (FosB) is a transcription factor induced by drugs of addiction [29]. The FosB delta variant (ΔFosB) is a truncated form of FosB with high stability, which accumulates with repeated exposure to drugs of addiction [30]. FosB and Fos family of proteins are induced rapidly and transiently in specific brain regions by drugs of addiction, most notably in the NAc and dorsal striatum. However, with chronic exposure to drugs of addiction, modified isoforms of ΔFosB accumulate in certain brain regions for several weeks after drug cessation, due to their long half-lives and their resistance to tolerance as compared to other FosB family proteins [31]. Induction of ΔFosB in the dynorphin-positive medium spiny neurons of the NAc has been shown to cause increased sensitization to the drug effects as well as resulting in incentive salience and predisposition to withdrawal symptoms and relapse [31,32]. In our lab, M. Xiong et al. [33] found an upregulation of ΔFosB protein in NAc with propofol administration, comparable with levels found after ethanol and nicotine administration. Drugs were administered via intraperitoneal injection twice a day for 7 days and NAc levels of ΔFosB were compared through protein and mRNA measurements via Western blot analysis and quantitative real-time polymerase chain reaction, respectively. There was also an upregulation of dopamine receptor D1 (drD1) which is an upstream signal molecule of ΔFosB within the addictive mesolimbic circuitry.

K-Y. Li et al. [34] studied the effects of nanomolar (nM) concentrations of propofol on VTA neurons, which coincides with the minute concentrations present in the air of operating rooms, thus emphasizing on the involvement of second-hand exposure to propofol. It was observed that 1 nM propofol increased the frequency but not the amplitude of spontaneous excitatory post-synaptic current (EPSC) while increasing the amplitude but not the paired pulse ratio of evoked EPSC in VTA dopamine neurons, all of which depict a presynaptic mechanism. This effect was blocked by drD1 antagonist. In a nutshell, it was inferred that nanomolar concentrations of propofol, via dopamine D1 receptors in the glutamatergic terminals on to VTA neurons, can increase excitability of VTA dopaminergic neurons. However, when M. Xiong et al. [35] extended this observation to examine the levels of propofol in anesthesiologists exposed to expired gases of patients undergoing propofol-based intravenous sedation, we did not find any significant difference. However, this study used a cut-off value of 50 ng/mL and hence the possibility of lower levels of blood propofol cannot be excluded. Also, this study being performed in a well-ventilated operating room cannot be applied to remote location procedure rooms which perform the majority of propofol sedation cases.

Dopamine and cyclic-adenosine monophosphate (c-AMP)-regulated phosphoprotein of apparent Mr 32000 (DARPP-32) is positioned to play a key factor in either mediating or modulating the short-, and perhaps long-term effect of drug of abuse such as nicotine, ethanol, cocaine or amphetamines [36]. A study by Pavkovic et al. [37] looked at the effect of propofol administration on several target molecules which are also affected by other addictive drugs. Western blot and immunohistochemistry was performed on target brain regions namely the medial prefrontal cortex, the striatum, and the thalamus, 24 to 48 h after propofol anesthesia. Molecular targets that were examined included drD1 expression; dopamine release; FosB and pDARPP-32 positive cells; and activity of calcium/calmodulin-dependent protein kinase II-α (CaMKII α), a biochemical sensor of synaptic activity, which in turn causes behavioral sensitization [38,39]. These studies found significant increase in the CaMKII α in the prefrontal cortex and striatum 24 h after exposure to propofol anesthesia. There was also significant increase in the number of FosB and pDARPP-32 positive cells in the paraventricular nucleus of the thalamus (PVT), which is consistent with studies performed in other drugs of addiction.

Some research groups also present the plausible role of other neurotransmitters and receptor substrates in promoting propofol addiction. For example, working along the lines of previous experiments which have linked addiction with glucocorticoid receptor signaling [40,41], some of the recent studies have also associated the abuse potential of propofol with the glucocorticoid system. Intra NAc administration of dexamethasone, a glucocorticoid receptor agonist increased the propofol addictive behavior in rats. This was further associated with upregulation of drD1 in NAc [42,43]. In another study, the Nitric oxide system was seen to play a functional role in anesthetic and locomotor stimulant effects of propofol [44,45]. Shahzadi et al. [20] showed that propofol-induced conditioned place preference (CPP), one of the behavioral test for rodents, was attenuated by inhibition of nitric oxide synthetase.

Drugs of addiction such as ethanol inhibit N-methyl-D-aspartate receptors (NMDAR) in the NAc after initial acute exposure. Inhibition of NMDA receptors is associated with activation of mammalian target of rapamycin complex 1 (mTORC1), a kinase responsible for alcohol associated synaptic plasticity, learning and memory in drD1 expressing NAc neurons. On the contrary, repeated cycles of alcohol cause long-term potentiation of NMDAR in striatal cells [46,47]. Propofol is also seen to inhibit NMDAR NR1 subunit phosphorylation at Ser897 and Ser896 through a signaling mechanism involving protein phosphatase 2A. However, this effect was observed in cortical neurons and it will be interesting to know how the NAc NMDA are affected in acute and chronic administration of propofol [48,49].

While assessing the function of glycine receptors in anesthesia-induced hypnosis, we observed that strychnine, a glycine receptor antagonist, reduced the LORR (loss of righting reflex), a marker of the hypnotic state induced by propofol [50]. In a study by Molander and colleagues [51], reversed microdialysis of glycine receptor agonist into the NAc increased release of NAc dopamine while infusion of glycine receptor antagonist decreased dopamine levels. Glycine receptors have also been involved in dopamine-enhancing effects of addictive drugs such as ethanol, tetrahydrocannabinol and nicotine [52,53]. Glycine receptors, thus playing a part in propofol induced hypnosis, could possibly play a part in its addiction circuitry too. On the other hand, GABA receptor has been implicated in developing synaptic plasticity to benzodiazepines, particularly α2 and α3 subunits containing GABA_A receptor, which cause a disinhibition of dopamine neurons as observed with other drugs of abuse [54,55]. The principle site of action of propofol being on the GABA_A receptor, this receptor can be another plausible substrate involved in propofol addiction mechanism too.

Recent studies explore the role of micro-RNAs in the addiction cycle of drugs [56,57]. Micro-RNAs are endogenous, small, non-coding RNAs that negatively regulate expression of multiple genes in a cell via degradation or translational inhibition of the target mRNA. Particularly, Li et al. [58] in their molecular study observed that downregulation of miRNA during alcohol dependence causes increased drD1 and ΔFosB expression observed during alcohol dependence, with ΔFosB being a downstream signal molecule for drD1. This increased expression can be inhibited by overexpression of miR382 (MicroRNA 382), in turn decreasing the voluntary intake as well as preference for ethanol. Whether propofol addiction also has a characteristic to regulate the microRNAs will be interesting to investigate in future especially in the light of similarity in terms of increased expression of drD1 and ΔFosB seen with propofol studies.

In a nutshell, despite having distinct targets, different drugs of addiction share the common reward pathway by enhancing synaptic secretion of dopamine from the VTA on to the NAc [25]. Propofol also increases the NAc dopamine levels following acute exposure and further modulates the VTA-NAc circuit following repeated exposure (). It will be helpful to know which of the different receptor targets of propofol act as the primary substrate re-enforcing the addictive potential of propofol. Subsequently, exploring the possibility and mechanism bridging the synaptic plasticity-induced changes by repeated propofol use and the resultant addictive phenotype will be of paramount importance in determining the significance of the proposed future regulatory recommendations on propofol use.

Effects of acute and repeated administration of propofol on the mesolimbic system. (A) Homeostatic state of body: The Ventral Tegmental Area-Nucleus Accumbens (VTA-NAc) circuit is a part of mesolimbic pathway and in homeostatic state of the body is involved in mediating individual’s responses to natural rewards like food, water, sex, and nurturing. This circuit comprises of dopamine neuron cell bodies in the Ventral Tegmantal Area (VTA) and their axons terminate in the Nucleus Accumbens (NAc) [59]. (B) Acute administration of propofol: Nanomolar (0.1–1 nM) concentrations of propofol enhanced VTA dopamine neuron activity by increasing the glutamatergic transmission to VTA dopamine neurons via presynaptic D1 dopamine receptors. This increased Dopaminergic (DA) neuron’s activity may cause increase dopamine levels in the NAc [34]. As such, acute intraperitoneal administration of sub-anesthetic and anesthetic doses of propofol resulted in increased dopamine levels in NAc [27]. Dopamine release in the NAc has been associated with motivation, reinforcement and reward processing [60,61]. (C) Repeated administration of propofol: Repeated intraperitoneal injection of propofol resulted in upregulation of dopamine receptor D1 and its downstream signaling molecules phosphorylated-EKR (p-ERK) and thereby the oncogene homolog B delta variant (ΔFosB) in the NAc [33,62]. The neuronal and synaptic plasticity in the VTA-NAc circuit, as seen with other drugs of abuse [25,26], may play a role in development of these changes. However, any experimental verification to support this theory remains to be elucidated. ΔFosB has been demonstrated to contribute to drug addiction by regulating expression of target genes in the reward pathway [31,32]. This evidence may hint towards a similar mechanism underlying propofol addiction and thus needs further research supporting this proposition.

​Statement on Safe Use of Propofol

Developed By: Committee on Ambulatory Surgical Care
Last Amended: October 23, 2019 (original approval: October 27, 2004)

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Because sedation is a continuum, it is not always possible to predict how an individual patient will respond.   Due to the potential for rapid, profound changes in sedative/anesthetic depth and the lack of antagonist medications, agents such as propofol require special attention.  Even if moderate sedation is intended, patients receiving propofol should receive care consistent with that required for deep sedation.

The Society believes that the involvement of an anesthesiologist in the care of every patient undergoing anesthesia is optimal.  However, when this is not possible, non-anesthesia personnel who administer propofol should be qualified to rescue* patients whose level of sedation becomes deeper than initially intended and who enter, if briefly, a state of general anesthesia.**

• The physician responsible for the use of sedation/anesthesia should have the education and training to manage the potential medical complications of sedation/anesthesia.  The physician should be proficient in airway management, have advanced life support skills appropriate for the patient population, and understand the pharmacology of the drugs used.   
The physician should be physically present throughout the sedation and remain immediately available until the patient is medically discharged from the post procedure recovery area.
• 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, as well as the ability to assist in the management of complications.
The practitioner monitoring the patient should be present throughout the procedure and be completely dedicated to that task.
• During the administration of propofol, patients should be monitored without interruption to assess level of consciousness, and to identify early signs of hypotension, bradycardia, apnea, airway obstruction and/or oxygen desaturation.  Ventilation, oxygen saturation, heart rate and blood pressure should be monitored at regular and frequent intervals.  Monitoring for the presence of exhaled carbon dioxide should be utilized unless invalidated by the nature of the patient, procedure or equipment because movement of the chest will not dependably identify airway obstruction or apnea.
• Age-appropriate equipment must be immediately available for the maintenance of a patent airway, oxygen enrichment and artificial ventilation in addition to circulatory resuscitation.

The Warnings section of the drug’s package insert (Diprivan®, AstraZeneca 02/14, accessed  02/19) states that propofol used for sedation or anesthesia “should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure.”  Patients should be continuously monitored, and facilities for maintenance of a patent airway, artificial ventilation, and oxygen enrichment and circulatory resuscitation must be immediately available.”

In addition, some states have prescriptive regulations concerning the administration of propofol.  There are different considerations when propofol is used for sedation of intubated, ventilated patients in a critical care setting.

For additional information on the continuum of sedation and on sedation by non-anesthesiologists, refer to the American Society of Anesthesiologists’ documents “Continuum of Depth of Sedation: Definition of General Anesthesia and Levels of Sedation/Analgesia” and “Practice Guidelines for Sedation and Analgesia by Non-Anesthesiologists”, ”Statement on Granting Privileges for Administration of Moderate Sedation to Practitioners Who Are Not Anesthesia Professionals”, and “Statement on Granting Privileges to Non-Anesthesiologist Practitioners for Personally Administering Deep Sedation or Supervising Deep Sedation by Individuals Who Are Not Anesthesia Professionals”.   ASA’s documents that address additional perioperative care issues are the “Guidelines for Office-Based Anesthesia,” “Guidelines for Ambulatory Anesthesia and Surgery” and “Practice Guidelines for Preoperative Fasting and the Use of Pharmacologic Agents to Reduce the Risk of Pulmonary Aspiration.”  All ASA documents can be found on the Web site, <www.ASAhq.org>.

* Rescue of a patient from a deeper level of sedation than intended is an intervention by a practitioner proficient in airway management and advanced life support.  The qualified practitioner corrects adverse physiologic consequences of the deeper-than-intended level of sedation (such as hypoventilation, hypoxia and hypotension) and returns the patient to the originally intended level.  It is not appropriate to continue the procedure at an unintended level of sedation.

** The statement in the AANA-ASA Joint Statement Regarding Propofol Administration, dated April 14, 2004, that reads,
“Whenever propofol is used for sedation/anesthesia, it should be administered only by persons trained in the administration of general anesthesia, who are not simultaneously involved in these surgical or diagnostic procedures.   This restriction is concordant with specific language in the propofol package insert, and failure to follow these recommendations could put patients at increased risk of significant injury or death.”

Act-Propofol – Uses, Side Effects, Interactions

How does this medication work? What will it do for me?

Propofol belongs to a class of medications known as hypnotics or anaesthetics. Hypnotics cause sleep and reduced sensitivity to pain by reducing the movement of pain messages through the nerves. They may cause partial or complete unconsciousness.

Propofol is used to induce and maintain sleep as part of anesthesia during surgery for adults and children 3 years of age and older. It may be used for adults before an uncomfortable procedure, to relax and reduce awareness but not cause deep sleep. This is referred to as conscious sedation. Propofol is also used to reduce awareness and cause sleep for adults who are being treated in an intensive care unit. This reduces awareness of surroundings and thus reduces the stress on the body, allowing recovery.

This medication may be available under multiple brand names and/or in several different forms. Any specific brand name of this medication may not be available in all of the forms or approved for all of the conditions discussed here. As well, some forms of this medication may not be used for all of the conditions discussed here.

Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. If you have not discussed this with your doctor or are not sure why you are receiving this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.

Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.

What form(s) does this medication come in?

Each 1 mL of white, oil-in-water emulsion contains 10 mL of propofol. Nonmedicinal ingredients: egg phospholipids (12 mg/mL), glycerin (22.5 mg/mL), sodium benzoate (1 mg/mL), soybean oil (100 mg/mL), and water for injection with sodium hydroxide to adjust pH.

How should I use this medication?

The dose of propofol used depends on why the medication is being given. Your doctor will calculate the appropriate dose based on body weight. Propofol is given intravenously (through a vein) by an anesthetist (a doctor who specializes anesthesia).

Propofol should only be used by doctors who have experience with anesthesia and using propofol. You should be continuously monitored and facilities for maintenance of a person’s airway, artificial ventilation, and oxygen enrichment and circulatory resuscitation must be immediately available.

Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are taking the medication without consulting your doctor.

Store this medication at room temperature, protect it from freezing and keep it out of the reach of children.

Strict aseptic techniques must always be maintained during handling as propofol is a single-use injectable product and contains no antimicrobial preservatives. The vehicle is capable of supporting rapid growth of microorganisms. Failure to follow aseptic handling procedures may result in microbial contamination causing serious infections which could lead to life-threatening illness such as septic shock.

Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.

Who should NOT take this medication?

Do not use this medication if you:

• are allergic to propofol or any ingredients of this medication
• are 18 years of age or younger receiving intensive care
• have any contraindications to sedation or general anaesthesia

What side effects are possible with this medication?

Many medications can cause side effects. A side effect is an unwanted response to a medication when it is used in normal doses. Side effects can be mild or severe, temporary or permanent.

The side effects listed below are not experienced by everyone who receives this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.

The following side effects have been reported by at least 1% of people receiving this medication. Many of these side effects can be managed, and some may go away on their own over time.

Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.

• decreased or increased heart rate
• dizziness
• flushing
• headache
• heat or pain at the injection site
• irregular heartbeat
• low blood pressure
• nausea
• rash
• vomiting

Although most of the side effects listed below don’t happen very often, they could lead to serious problems if you do not seek medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

• difficulty breathing
• signs of muscle damage (e.g., unexplained muscle pain, tenderness, or weakness or brown or discoloured urine)
• muscle spasms

Stop using the medication and seek immediate medical attention if any of the following occur:

• seizures
• symptoms of a heart attack (e.g., chest pain, difficulty breathing, pain down left arm)
• symptoms of an allergic reaction (e.g., difficulty breathing, sweating, swelling of the face or throat, hives)
• symptoms of low blood sugar (e.g., dizziness, confusion, weakness, sweating)

Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are using this medication.

Are there any other precautions or warnings for this medication?

Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.

Drowsiness/reduced alertness: Propofol will cause reduced alertness and cause a person to be drowsy even after they have awakened. If you have received propofol as part of an outpatient procedure, you should not drive or operate machinery until the effects of propofol have completely passed.

Heart disease: Propofol can caused decreased heart rate or blood pressure. If you have heart disease, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Impaired fat (lipid) metabolism: If you have impaired lipid metabolism (e.g., high lipid levels associated with diabetes, pancreatitis), discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Impaired kidney and liver function: The safety and effectiveness of using this medication if you have impaired kidney and liver function have not been established.

Seizures: If you have seizures or a history of seizures, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Pregnancy: There is evidence that a baby who is exposed to propofol before birth may experience impaired brain development. This medication should not be used during pregnancy unless the benefits outweigh the risks. If you are or may be pregnant and require this medication, contact your doctor immediately.

Breast-feeding: This medication passes into breast milk. If you are a breast-feeding mother and are taking propofol, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

Children: The safety and effectiveness of this medication have not been established for children less than 3 years of age. There is evidence that the use of propofol to treat young children may cause decreased or impaired brain development. Propofol may be used as part of anesthesia for children 3 years of age and older. It should not be used for children under the age of 18 as sedation in intensive care or conscious sedation.

Seniors: Seniors may be much more likely to experience side effects of this medication and may require lower doses.

What other drugs could interact with this medication?

There may be an interaction between propofol and any of the following:

• alcohol
• aldesleukin
• aliskiren
• alpha-agonists (e.g., clonidine, methyldopa)
• alpha-blockers (e.g., alfuzosin, doxazosin, tamsulosin)
• angiotensin converting enzyme inhibitors (ACEIs; captopril, enalapril, ramipril)
• angiotensin receptor blockers (ARBs; e. g., candesartan, irbesartan, losartan)
• amifostine
• antiarrhythmics (e.g., amiodarone, disopyramide, dronedarone, procainamide, quinidine)
• antihistamines (e.g., cetirizine, doxylamine, diphenhydramine, hydroxyzine, loratadine)
• antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
• azelastine
• barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
• benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
• beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
• brimonidine
• buprenorphine
• buspirone
• calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
• cannabis
• chloral hydrate
• diazoxide
• diuretics (water pills; e.g., furosemide, hydrochlorothiazide, triamterene)
• duloxetine
• efavirenz
• entacapone
• flibanserin
• general anaesthetics (medications to put you to sleep for surgery)
• guanfacine
• hydralazine
• levodopa
• lomitapide
• magnesium sulfate
• mifepristone
• minoxidil
• mirtazapine
• muscle relaxants (e. g., baclofen, cyclobenzaprine, methocarbamol, orphenadrine)
• nabilone
• narcotic pain relievers (e.g., codeine, fentanyl, morphine, oxycodone)
• nilotinib
• nitrates (e.g., nitroglycerin, isosorbide dinitrate, isosorbide mononitrate)
• obinutuzumab
• pentoxifylline
• phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
• pramipexole
• quinine
• rifampin
• riociguat
• ropinirole
• rotigotine
• scopolamine
• seizure medications (e.g., carbamazepine, clobazam, levetiracetam, phenobarbital, phenytoin, primidone, topiramate, valproic acid, zonisamide)
• selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, paroxetine, sertraline)
• sodium oxybate
• tapentadol
• tetrabenazine
• thalidomide
• tramadol
• trazodone
• tricyclic antidepressants (e. g., clomipramine, desipramine, imipramine)
• zolpidem
• zopiclone

If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:

• stop taking one of the medications,
• change one of the medications to another,
• change how you are taking one or both of the medications, or
• leave everything as is.

An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how any drug interactions are being managed or should be managed.

Medications other than those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.

All material copyright MediResource Inc. 1996 – 2021. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/drug/getdrug/Act-Propofol

Diprivan (propofol) dosing, indications, interactions, adverse effects, and more

90,000 propofol, thiopental and ketamine. What’s new?

In therapeutic doses, propofol moderately inhibits respiration. It also induces a dose-dependent decrease in blood pressure, mainly through a decrease in cardiac output and systemic vascular resistance. A unique property of propofol is its antiemetic effect , which is manifested in concentrations much less sedative. The induction dose, accompanied by loss of consciousness, is 1-2 mg / kg with a maintenance infusion rate 100-200 mcg / kg / min .For prolonged sedation, doses of from 25 to 75 mcg / kg / min are usually sufficient. At a propofol infusion rate of more than 30 μg / kg / min, patients develop amnesia. Compared to midazolam , when used as the main sedation drug, propofol is similarly or better controlled and provides faster awakening.
Propofol infusion syndrome is a rare but fatal complication associated with the infusion of propofol at a dose equal to or greater than 4 mg / kg / h for more than 48 hours. It was first described in children, but was subsequently observed in seriously ill adults. Clinical signs of propofol infusion syndrome are acute refractory bradycardia , leading to asystole, in the presence of one or more of the following: metabolic acidosis (base deficiency more than 10 mmol / L), acute rhabdomyolysis, liver enlargement, hyperlipidemia or fatty hepatosis [ Kam PC, Cardone D: Propofol infusion syndrome.Anesthesia 62: 690-701, 2007 ]. Other signs include: cardiomyopathy with acute heart failure, skeletal myopathy, hyperkalemia, liver enlargement, and lipemia [ Kang TM: Propofol infusion syndrome in critically ill patients. Ann Pharmacother 36: 1453-1456, 2002 ]. Theories about its causes include mitochondrial toxicity, mitochondrial defects, impaired tissue oxygenation, and carbohydrate deficiency. The main risk factors for the development of propofol infusion syndrome are probably reduced oxygen delivery to tissues, sepsis, severe brain damage and high doses of propofol.In some studies, an increase in lipemia was noted, probably associated with impaired hepatic regulation due to decreased oxygenation, low glucose levels, or a combination of these factors. In some cases an increase in lipemia was the first sign of the development of propofol infusion syndrome , and therefore it should not be considered as a harmless sign [ Ahlen K, Buckley CJ, Goodale DB, Pulsford AH: The “ propofol infusion syndrome “: The facts , their interpretation and implications for patient .Eur J Anesthesiol 23: 990-998, 2006 ].
Propofol is recommended for sedation in intensive care. However, there are also alternatives, such as inhalation sedation with sevoflurane or isoflurane using the AnaConDa device, read more here …

90,000 is it safe? And the children? / Habr

The device with everything necessary for anesthesia in children.

There is such a wonderful phobia in people who faced Soviet punitive dentistry in childhood – stomatophobia.Then it was believed that local anesthesia was invented for the faint of heart, and it was normal to endure the smell of burnt dentin and terrible pain for an hour. Despite the fact that now no sane dentist will heal without anesthesia, sad people still walk among us, traumatized by these memories. Sometimes such patients overpower themselves and come to an appointment with a panoramic dental X-ray. More precisely, with a dozen dilapidated roots and many infected purulent foci in the bone structure of the jaw.

If people have already got used to the idea that children should be treated under local anesthesia, then general anesthesia is still scary. Many people still remember the difficult recovery from anesthesia with nausea and “helicopters” during the use of heavy old drugs. And until now, people have a feeling that any general anesthesia is something extremely dangerous and even more unacceptable for use in children, except for emergency indications. In fact, everything has changed a lot.

In short, let’s talk about anesthesia in children.And also – about modern options with nitrous oxide, propofol and sevoflurane. They are very good, but remember that independent experiments with them may end up meeting with Kurt Cobain.

Anesthesia depth

Let’s generally figure out what anesthesia is. Our brain is a complex set of neurons that constantly exchange impulses with each other. Some substances can inhibit synaptic transmission between individual groups of neurons. Moreover, different substances have different mechanisms of action and their own characteristics.In fact, anesthesia is also one of the types of anesthesia. Only in contrast to the local shutdown of local pain neurons during local anesthesia, we partially “turn off the brain”.

As a result, general anesthesia is not like a complete “shutdown” of the brain. Rather, it is a kind of very deep sleep, from which you can wake up only when the anesthesiologist allows it. What is being suppressed first? To begin with, this is consciousness. The main purpose of general anesthesia is to reduce the stress level of the patient.We want to make sure that the entire treatment goes unnoticed for him and does not leave any unpleasant memories. In addition, pain sensitivity is suppressed and motor activity is inhibited. That is, with the correct anesthesia, the patient does not hurt, and he does not try to get up and leave, posing as a sleepwalker.

Of course, suppression of central nervous system functions should turn off only consciousness and pain, without affecting the important autonomous centers of regulation of heartbeat, respiration and vascular tone. Only experienced doctors can provide all this correctly.There are usually four degrees of depth of anesthesia:

1. Superficial anesthesia.
2. Light anesthesia.
3. Full anesthesia.
4. Superdeep anesthesia.

If necessary, the anesthesiologist can vary the degree of CNS depression, for example, to ask the patient to move the jaw correctly. This can be done when using propofol, for example. Or, conversely, increase the depth if the patient begins to worry.

Why are such methods needed at all, if there is a conditional local articaine, which can most often be dispensed with? First of all, the problem is panic fear and stomatophobia.A good patient is a calm patient, not one who, in horror, tries to run away and flinches at every movement of the doctor. This will not benefit the patient himself and will not help the doctor to cure him qualitatively. Additional arguments in favor of anesthesia will be a very pronounced gag reflex and a large amount of intervention. We can’t just inject anesthetic into a patient, especially a little one. Local anesthetic also has a limiting dosage for simultaneous administration, and, for example, bilateral conduction anesthesia in the lower jaw can cause difficulty breathing due to the complete shutdown of tongue sensitivity.And the most important thing is that even the most sensitive doctor will never agree with a child on the treatment of 15–20 teeth at the same time. Yes, it also happens when children don’t brush their teeth properly, eat buns and don’t go to the dentist.

Therefore, oddly enough, it is general anesthesia that can often be an easier and more comfortable choice for the little patient and the attending physician.

Key drugs for general anesthesia

Before we go into detail on how we use general anesthesia in children, let’s go over a few key drugs.These are nitrous oxide, propofol and sevoflurane (better known by the commercial name “Sevoran”). Without them, it is difficult to imagine modern safe general anesthesia with easy and quick awakening.

The correct use of modern methods is very important for the child to easily endure the anesthesia.

Nitrous oxide

Nitrous oxide has long been known exclusively as “laughing gas”.

The history of the medical use of nitrous oxide began in 1799, when a sophomore named Humphrey Davy, who became an eminent scientist, noticed that inhalation of this gas causes euphoria and intoxication.During the experiments, he accidentally drew attention to the fact that under the influence of gas, toothache disappears. Don’t ask what these experiments were. In 1844, Horace Wells performed the first dental surgeries under nitrous oxide anesthesia. Now it is one of the most common gases used to relieve pain sensitivity during small-scale manipulations.

Nitrous oxide has practically no toxic effects when used correctly. It is metabolized: 99.996% of the gas is excreted unchanged during exhalation.Because of this, its effects are very short and most often stop within a minute after stopping the flow. Its safety profile is so good that it is used for pain relief in children and pregnant women during childbirth. In the second case, it is used in the so-called “anesthesia on demand” mode, when a woman in labor, before the beginning of a contraction, takes several breaths of a mixture of nitrous oxide and oxygen from a mask of a special apparatus. In this case, the contraction is almost painless. Not as effective as with epidural anesthesia, but clears up much faster.

The main effects are achieved by antagonizing NMDA receptors. Many synthetic opiates, such as tramadol, act in a similar way. But unlike opiates, nitrous oxide is not addictive and does not suppress the respiratory center, which leads to its high safety profile. Also, according to a not entirely clear mechanism, endorphins are released, which triggers our internal mechanism for limiting pain – the antinociceptive system. At the same time, the analgesic effect is quite strong and is approximately equivalent in strength to 15 mg of morphine.But nitrous oxide alone is not enough to do anything with the teeth, so it is used in combination with local anesthesia.

Mild euphoria and increased mood are achieved by stimulating the release of dopamine, judging by the data of experiments on rats.

It also has an anxiolytic effect: it suppresses anxiety. In small doses, nitrous oxide increases the sensitivity of the GABAA receptors. The benzodiazepine anti-anxiety drugs work in much the same way. As a result, the patient’s anxiety decreases, he relaxes and shows slight drowsiness.There is also a slight anticonvulsant effect.

Overdose as such is also almost impossible. The main key point to watch out for is the patient’s saturation to prevent oxygen deprivation. Well, if there is no anesthesiologist nearby and the action takes place in a nightclub – so that the patient does not have time to knock and hit during his attack of Viking madness on protruding objects and guards.

Brief Summary: Treating teeth with nitrous oxide is fun and safe, as long as it does not involve very deep interventions.Then the pain still breaks through.

Propofol

Ampoule with propofol emulsion.

Propofol is another significant drug in the practice of an anesthesiologist. The drug has a milky white color due to the fact that it is not a solution, but an emulsion. The active substance itself is insoluble in normal saline solution, therefore it is introduced in the form of a stabilized emulsion with a phospholipid base.

The drug works interestingly. You have probably seen how in the films something is injected into the patient, and he instantly turns off.Propofol has exactly the same effect. Our brains are largely composed of fats, in which propofol is highly soluble. Therefore, the time from its introduction to loss of consciousness is only a few seconds. It takes literally a few heart beats to deliver the required dose of the drug to the central nervous system.

Interestingly, propofol has only a sedative effect, suppressing the activity of the central nervous system. At the same time, it does not suppress pain and tactile sensitivity. Therefore, it must be combined with local anesthetics.And he also has a very funny feature: it causes retrograde amnesia, that is, the last thing the patient remembers upon awakening is the events shortly before the drug was administered. Moreover, similar to sodium thiopental, propofol allows you to control patients to perform the simplest commands: stick out your tongue, close your mouth, open your mouth. That is, some contact remains, which is a big plus in some situations. Actually, it is precisely for this combination of amnesia and controllability that the same sodium thiopental was described in all spy novels as “truth serum.”In fact, a real interrogation would be difficult to conduct, as the patient is likely to simply hum something incoherent.

Just propofol – you feel everything, it hurts, you follow simple commands and you may even mumble incoherently: “Fuck off, I’m married”, but then you will forget everything. Propofol + topical remedy removes the pain from this situation, but you twitch and interfere with the doctor, your heart rate can accelerate dangerously with an incision. Propofol + the same sevoran remove the pain and allow you to control the situation completely, but even turn off the level of consciousness that allowed humming.

Sevoflurane

A pleasantly sweetish smelling gas with the common commercial name “Sevoran” is one of the most convenient and safe options for inhalation anesthesia, displacing halothane and isoflurane in modern anesthesiology. Has become widespread due to its excellent safety profile

and easy administration and recovery from anesthesia. With its appearance, the typical “helicopters” with vomiting for long hours after the operation, typical for the previous generations of drugs, have become a thing of the past.

Due to moderate relaxation of the respiratory muscles and general sedation, it suppresses the trigger zones of the cough and vomiting reflexes. This means that the doctor can work calmly without fear that the patient will suddenly start to vomit or cough during the process of delicate manipulations (for which gastroenterologists love him separately with FGDS). In this case, the anesthesiologist continuously monitors the patient’s blood pressure and oxygen saturation. It is important to avoid even the smallest lack of oxygen supply even in the smallest patients.

The laryngeal mask is inserted like this.

Most often it is used for the introduction of anesthesia in a mixture with nitrous oxide and oxygen. When the patient falls asleep, the face mask is changed to a laryngeal mask. Further, the patient’s breathing is controlled by mechanical ventilation. At the same time, the introduction of a laryngeal mask for inhalation anesthesia in children differs from that in adults. Children have a different structure of the larynx and different angles of introduction. For example, we always take into account the characteristics of children with a relatively short neck or malocclusion.A good doctor who works with children will do this as gently as possible – so that the child will not have any unpleasant sensations in the larynx after waking up.

Which type of anesthesia is better

So, we went over the main properties of drugs for general anesthesia. Now let’s take a look at which options are better in each case. Children are not the same, they are all different. Some child will calmly react to the insertion of a catheter at a very young age, and some will refuse a painless mask at the age of eight or nine.Therefore, we always carefully communicate with the baby himself and with his parents. This is necessary to establish a trusting contact between the doctor and the little patient. Without this, it will simply not be possible to work normally. At the same time, the most detailed information on the characteristics of the child’s health is collected so that the anesthesiologist can choose the most comfortable and safe option for general anesthesia.

Interestingly, children very quickly begin to trust doctors if they see that everything was painless and the tooth no longer bothers.As a rule, further treatment is much easier. We had a case when a girl fell from a swing in kindergarten, bumped and lost an artificial crown, which she had to put on almost three of us. As a result, she herself returned to the clinic with her parents, brought the crown in her palm and asked to return it to its place.

Local anesthesia only

Suitable for

: brave children of all ages who trust a doctor.

This option is a little past the main topic of our post, but I also want to mention it.If the child initially comes with a bunch of damaged teeth, and even for some reason intimidated by relatives, then such a scenario may not be possible. And it is necessary to treat. This is where the whole arsenal of means for general anesthesia will help us.

Local anesthesia and nitrous oxide

The child should have free nasal breathing. Nitrous oxide has a bunch of effects we want. It relaxes, eliminates anxiety, and lifts the mood a little. During treatment, the patient will be awake.At the same time, it will not be possible to anesthetize it in its pure form, it will still be painful to prepare the teeth. Therefore, we usually let the child breathe through a special mask that covers only the nose. Many people like it very much, plus we often tell stories about test pilots who also have special masks with breathing gas.

When the child has relaxed, you can already do the application anesthesia with the gel and then inject the main anesthetic. Unfortunately, under nitrous oxide, it will not be possible to do a large amount of intervention at once.Children get tired of lying with their mouths open, the mask begins to irritate. Therefore, this method is better suited for small one-stage interventions – one or two teeth. At the same time, we cannot increase the concentration above 50% for a child, we need to look for other, stronger, but safe drugs.

Local anesthesia and sevoflurane

Sevoflurane can be given to school-age children without any problems, but there are several nuances. With older children, it is easier to negotiate awake local anesthesia or intravenous propofol.There are several advantages to a complete shutdown of consciousness, which does not happen with the same nitrous oxide.

Firstly, the child does not experience wild stress and does not earn stomatophobia for the rest of his life. There is nothing worse than a stern nurse kneeling on you and holding a mouth speculum while the doctor frantically tries to do something in the mouth.

Secondly, it allows for high-quality treatment, when the doctor is sure that the patient will not twitch, start waving his tongue, or try to escape in the middle of an important stage.

The anesthesiologist can vary the depth of anesthesia by changing the composition of the gas mixture. This makes it possible to accurately monitor the patient’s vital signs and provide the desired level of relaxation and immobility. If you need to treat caries, then there is no point in additionally injecting an anesthetic. The degree of CNS suppression is sufficient to make the patient comfortable. If it is planned to treat pulpitis or periodontitis, to remove teeth, then we additionally introduce a local anesthetic. Otherwise, painful impulses will still reach the “sleeping” brain and cause an adrenaline rush and involuntary movements.With a complete shutdown of consciousness, we can carry out any amount of intervention. And we are talking not only about some painful things like the treatment of six carious teeth in one go, but also, for example, about taking accurate impressions for the subsequent manufacture of orthopedic and orthodontic structures. Try convincing a sobbing four-year-old to sit still while the silicone in the impression spoon hardens in his mouth.

Local anesthesia and propofol

A child under three years old is prohibited from using this.We have already discussed the features of propofol above. It has no analgesic effect, but only suppresses consciousness. That is why it needs to be supplemented with local anesthesia, as if the patient were awake. But its main plus when working with the same teenagers is that they can perform simple commands. This makes the doctor’s job easier. You can lower the depth of anesthesia and ask to bite the template, model the structure according to the bite, or something similar. It is important for the dentist not only to depict fillings at the site of carious defects, but to carefully model the occlusal ratios of the jaws so that after treatment the biomechanics of chewing is ideal.

FAQ

Can you eat before anesthesia?

No. And parents need not just tell the child about this, but make sure that he does not gorge himself on cookies from his secret reserves. The child is hungry, he will try to eat at least something. Anesthesia on a full stomach threatens with vomiting during treatment or upon awakening. If it is “in the process of treatment”, then the substance can block the airways, which is not needed by anyone.

How easily is the anesthesia tolerated?

If all the protocols are followed, the process is monitored by an experienced anesthesiologist, then everything goes without problems and special side effects.To do this, we follow all protocols and everything that is necessary for complete security. For example, study

, which says that with proper anesthesia with propofol and isoflurane, all side effects after waking up last less than a day.

But sometimes our hair just stands on end when mom comes to our clinic after not the most correct anesthesia in another place. We usually catch such parents with a load of food for a week and the moral expectation of three days of continuous vomiting and dizziness upon waking up.Here you immediately realize that in another place the general anesthesia did not go quite right.

Will he wake up for sure?

Yes. This is not a matter of likelihood, it is a matter of adherence to protocol. It is necessary to check the equipment, have a doctor of the required qualifications, understand the characteristics of a particular patient. Then there will be no surprises. The process is closely monitored by an anesthesiologist-resuscitator who is ready to intervene at any time and adjust the parameters of anesthesia. He knows how to smoothly enter and remove from anesthesia, knows all the nuances of resuscitation measures in children.

I was told about doctors who are against anesthesia

Yes, it happens. But I think that they are not entirely right and they simply do not have a good anesthesiologist. The safety of general anesthesia for the health and intelligence of the baby has been confirmed by numerous studies. For example, they took 90,099 19,296 children

and studied their development after many anesthesia underwent up to the age of 20. The results prove that everything is fine and that the children are no different from their peers.At the same time, many sources nevertheless come to the

idea

that repeated anesthesia at the age of up to two years is undesirable.

In general, sometimes misunderstanding and fear of general anesthesia take strange forms among some doctors. In my memory, there was one wild case when a doctor tried to save children from a terrible anesthesia, replacing it with a temporary strangulation with a towel. Binds, restrains and heals half-smothered. Such a kind doctor. Moreover, in fact, she uses the variant of rausch anesthesia.But it was only relevant several hundred years ago, when even etheric anesthesia was not invented, and the only option to carry out a conditional amputation was a precisely calculated blow with a wooden mallet on the crown. But it was difficult to control the “depth” of such anesthesia and guarantee a successful awakening.

What about the eyes during treatment?

The eyes dry only with deep anesthesia, in our case they are sufficiently moistened with a tear. The patient’s eyelids are fixed with a special plaster.So the eyes remain closed, and the mucous membrane does not dry out. Well, the risk is excluded that something can get into them.

Will hair fall out after surgery?

I know it sounds strange, but this is what parents ask. Here’s the thing: if you lose a lot of blood during surgery, hair loss can be a side effect. But when a mistake is made in surgery, it is most often attributed to uncontrollable factors in the spirit of: “This is such a drug for anesthesia”, and not to the fact that someone could not perform the manipulation on time or did not make the right decision.And the anesthesiologist has nothing to do with it.

Will it affect the child’s memory, will it damage the brain?

It will not affect in any way – neither good nor bad. The anesthesiologist carefully monitors the oxygen saturation level to ensure that the young brain receives enough oxygen. The device does not supply pure gas, but mixed with oxygen. All sensors are built into the ventilator. If necessary, the doctor can, for example, adjust the composition of the gas mixture. All drugs have an excellent safety profile and a lot of research confirming their safety when used in pediatric patients.We also know how to work quickly. If we used to work on very voluminous interventions for six hours, then up to four, up to three, now the average duration is no more than 2.5 hours: this, in particular, is why we need technology and a professional team.

Will he have bad dreams?

Will not. The child will not remember the process of anesthesia itself and, most likely, some short period before it. Just try not to scare him again yourself: children are very impressionable.Then we will try to make everything as comfortable as possible for him: he fell asleep, woke up, and then we played.

Why is it so important not to scare a child

The most difficult thing in dentistry is not to scare a child. Unfortunately, this is often done for us by some strange grandparents who scare the child with doctors. Please, never tell children things like: “If you eat candy, you ruin your teeth. And then the doctor will be a terrible drill to drill your teeth. ” Sooner or later, the little patient will have to face the dentist.And we would like him to trust us, and not run away screaming at the sight of a white robe. Otherwise, everything can end up with persistent stomatophobia, a mouth full of prostheses and a bunch of problems for life.

P.S. In previous posts about palatal dilators and the scientific approach to dentistry, you asked about the clinic. If you want to have your teeth treated with us, then say “I am from Habr”, there will be a small 5% discount. 90,099 90,000 The mystery of people who are not treated with local anesthesia

• Chris Baranyuk
• BBC Future

January 24, 2017

Photo by Thinkstock

Some people don’t respond to local anesthesia, which means that they have to endure various dental and medical procedures without pain relief.The BBC Future columnist tried to understand why this is happening.

Laurie Lemon has an unusual feature that surprises many doctors. She once went to the Mayo Clinic in Jacksonville, Florida to have a lipoma removed, a benign subcutaneous tumor of fatty deposits that had developed on her elbow.

For this procedure, it was necessary to anesthetize the area around the tumor, but for some inexplicable reason this was not possible.

“Whatever drugs and routes they used, none of them worked,” she says.

Clinic anesthetist Stephen Klendenen confirms this. “Her nerves were literally flooded with local anesthetic, but it didn’t help,” he recalls.

Perhaps the doctors were surprised, but not Lemon. She faced the problem of resistance to local anesthetics all her adult life.

The first case occurred decades ago at a dentist’s appointment, when she was about seven years old.

“The doctors began to perform all the necessary actions, and I, being a very meek child, just raised my hand and said that I feel everything,” she says.

The second injection of local anesthetic also had no effect. “I ended up just screaming and crying nonstop,” Lemon recalls.

Clendenen, personally convinced of the consequences of this resistance to anesthetics for his patient, decided to study this issue in more detail.

In the medical literature, he found only a few references to strange cases in which patients stated that the local anesthetic did not work on them.

It turned out that no one had any idea what was wrong with these patients. He did not come across any information about what mechanisms cause this resistance, nor about the methods of its treatment.

However, new genetic research involving Lemon and her family may help us unravel this mystery.

Photo author, Thinkstock

Photo caption,

Patients with resistance to local anesthesia can choose general anesthesia, which is a much more complex procedure

Alan Hakim and his colleagues at University College London Hospital were among the first scientists to raise this question.

Hakim assisted in the management of a clinic for people with Ehlers-Danlos Syndrome (EDS). This is a group of very rare genetic diseases characterized by defects in connective tissue and accompanied by hypermobility of the joints, bruising and fatigue.

Hakim found that some of these patients complained of resistance to local anesthesia. The pain relief did not work on them and they had to endure the pain.

“It became clear to us that this question should be asked about every patient admitted to the clinic,” recalls Hakim, who co-authored a summary of the study in 2005.

Hakim wrote about the problem 11 years ago, but he says that no formal medical investigation into the causes of local anesthetic resistance has been carried out in those cases.

However, several theories have emerged. One hypothesis is that the tissues in patients with EDD are slightly different from those in healthy people, and this may affect the absorption of the anesthetic.

Local anesthesia is achieved by blocking sodium channels. These channels provide the passage of positively charged sodium ions – and with them the sensation of pain – to the nerve cells.

However, the mechanics of this process are not fully understood. If we can figure out all the details, we can understand why certain drugs – for example, articaine rather than lidocaine – work better for some patients.

Photo Credit, Science Photo Library

Photo Caption,

Doctors are still trying to understand how differences in the structure of the peripheral nervous system can lead to these strange symptoms

According to one theory, articaine is more effective because it dissolves better in fats (lipids) and better penetrates the nerve membranes.

In addition, it is possible that the nerve endings in these patients may be slightly away from where they should normally be located. For example, dentists sometimes solve this problem by changing the injection site.

Sometimes a local anesthetic is injected subcutaneously into the tissue (called infiltration) and sometimes directly into or near the nerve (nerve block).

In the latter case, the anesthetic spreads from the blockage site along the nervous system, penetrating directly into the nerve cells.

This method is used in dentistry if the tooth has to be drilled for a very long time, since other nerves may be affected, and the anesthetic does not need to penetrate many layers of tissue to reach them.

However, there are practically no reliable data on this. The authors of articles describing the reasons for the resistance of patients with EDS to local anesthetics do not go into such details.

“They do not specify which method was ineffective – infiltration or nerve block,” says Joel Weaver, an anesthesiologist at Ohio State University.

Hakim says the work he and his colleagues have done has helped doctors and dentists understand that local anesthetic resistance is a real problem.

However, many still have not heard of it and react skeptically when first told that such a phenomenon exists.

Jenny Morrison, a nurse who works with EDD patients and suffers from this syndrome herself, knows this firsthand.

“The anesthesia only lasts for a few minutes and wears off very quickly,” she says.“It doesn’t work for someone at all, but for me it takes about 10 minutes.”

Patients told her that their doctor or dentist simply did not believe when they were told that local anesthesia did not work.

Ehlers- Danlos UK has released information that patients can show their doctor to explain the problem from a modern medical perspective

Morrison thinks it might help, but doctors’ attitudes about the problem will not change until large-scale official research confirms the existence of this phenomenon in a fairly large sample of patients.

“It seems to me that doctors will not accept this until there is sufficient evidence,” she says.

Laurie Lemon says she has experienced similar attitudes as well. In addition to the dentist and other later procedures, she recalls other surgical-related experiences in which she had to endure pain.

She gives an example of cardiac catheterization, in which a long, thin tube is inserted into a patient’s heart through veins.

“I had to undergo a cardiac catheterization, although I felt everything that was being done to me,” she says.“You won’t wish that on anyone.”

Missense Mutation

But in Lemon’s case, there’s something else surprising: she’s never been diagnosed with SED. Could there be other reasons for her resistance to anesthetics?

Just like that Stephen Klendenen asked himself the question as soon as he began to study her medical record.

His son Nathan, who worked at Yale University School of Medicine, suggested that genetics may be to blame for everything. believe that anesthetic resistance is much more common than we think.

They asked other members of the Lemon family if they had a similar problem. It turned out that her mother and her maternal half-sister had resistance to anesthesia, although not so pronounced, while her father did not.

The next step was to analyze the genome of family members. When Klendenen and his colleagues performed it, they discovered a genetic defect associated with one of the sodium channels known as “sodium 1.5”.

A mutated gene called SCN5A is responsible for the production of the NaV1 protein.5, which is the main component of this channel.

This type of mutation is called a “missense mutation”, which means that in people with a similar genetic trait, one of the amino acids in this protein is replaced by another, and this can affect its function.

For example, in people with sickle cell disease, a similar mutation leads to the formation of defective hemoglobin, a protein responsible for the transfer of oxygen in the blood.

“We looked at the genetic side of the phenomenon and were surprised: her mother had the same genetic defect,” says Klendenen.

The same was found in her maternal half-sister, but not in her father, who did not complain of resistance to anesthesia.

However, sodium channels 1.5 have been studied in detail only in cardiac tissue, and not in peripheral nerves to which local anesthesia is applied.

Photo author, Thinkstock

Photo caption,

Dentists can use different drugs or inject anesthetic into another part of the tissue, but this does not always give the desired result

However, a chemical test immediately showed that sodium channels 1.5 are also present in peripheral nerves, which means that, in theory, the genetic defect associated with them could suppress the effect of the anesthetic on the corresponding parts of the body.

The exact effect of this mutation is not yet known, but it can be assumed that because of it, sodium channels remain open, and, despite the use of local anesthetic, signals continue to enter the brain.

Typically, the anesthetic blocks the passage of sodium through the canal and the nerve does not transmit the pain signal.However, Klendenen admits that the details of this mechanism are still a mystery.

Klendenen says that after he presented his work at a recent conference, he was contacted by several doctors who also had patients with then unexplained resistance to local anesthesia.

A doctor told him that he once performed at least five nerve block procedures on a patient, but never got any results.

Alan Hakim calls this study amazing.He notes that by identifying genetic differences that can affect ion channels in the nervous system, we can improve the way we treat patients with anesthesia resistance.

“This can be very helpful in determining which medications should be used and how effective they will be,” he says.

Hakim emphasizes that the sample size in the current study is limited to just one household and therefore the result will need to be double-checked.

Klendenen plans to recruit other patients suffering from topical antibiotic resistance to the study to see if they have this genetic trait.

He also wants to study the effect of a topical antibiotic on cells with this genetic defect.

Lemon highly praises his work and the Mayo Clinic. She says that she is simply afraid to tell doctors that something may go wrong during surgical procedures, but she tries to treat it with humor.

“I feel like one of the X-Men,” she jokes. “I also have mutated genes.”

For those who have to endure invasive procedures in the doctor’s office without anesthesia, or who use general anesthesia just to get their teeth done, there may soon be reason to hope for a change.

“It’s very important that this issue is not hushed up,” says Klendenen. “People don’t believe these patients, which is unfortunate. Even some of my colleagues I’ve talked to about this say they don’t believe it.”

Clinical Study Procedural Sedation: Propofol – Clinical Trials Registry

Dental treatment in a dream in Ryazan at favorable prices

The state of the oral cavity is one of the fundamental factors of good human health.Oral infections directly affect hearing, vision, digestion and facial skin. Diseased teeth can cause headaches and inflammation of the joints and lymph nodes. Every modern person should make a good habit of regular visits to the dentist.

Treatment without pain and fear

Fear of dental treatment is not a fictional excuse. The problem is a serious obstacle to visiting the clinic and often leads to serious consequences. The fear of pain and a drill is familiar to everyone.Fear is especially deeply rooted in those patients who have had to treat sore teeth or remove nerves without pain relief.

We are bringing to your attention a new service in the dental field – dental treatment in a dream . This approach has not yet become widespread, and requires serious training of the clinic staff and obtaining permission for this type of activity. With us, you can do dental treatment without pain and fear today.

Indications for the procedure

Nowadays every dentistry has good pain relievers, and the treatment procedure is quite simple.Not every patient is recommended dental treatment under anesthesia , a number of cases can be distinguished when it is better to choose this type of anesthesia:

• children up to 4-5 years old;

90,122 patients with irresistible phobia;

• low pain threshold;
• complex and long-term impact;
• severe painful inflammation.

If a child is experiencing anxiety, violence can disrupt mental health and lead to future problems.In no case should you let the development of caries take its course, waiting for the child to grow up. Any oral problems need to be addressed immediately. Pain-free dental treatment helps children and parents avoid stress.

Fear of the dentist often leads to serious neglected cases, when a person gets used to the loss of teeth and is ready to exist in such a state all his life. You no longer have to put up with tooth decay. Just decide for a consultation, and you will understand that your health and beauty are very close.

Guaranteed safety

You should not be afraid of the word anesthesia, now there is nothing to be afraid of. The sedation method is used for dental treatment. The patient is immersed in sleep with the help of hypnotics. The doctor selects the composition, depending on the duration of the upcoming procedure. The pain reliever is given separately. The doctor controls such a dream and can interrupt it at any moment, the sleep is safe and harmless.

In order to ensure safety, the anesthesiologist must communicate with the patient during the consultation, he concludes whether the treatment is right for you or tooth extraction under anesthesia.

Our clinic has received a license to use the corresponding medicines. Modern equipment diagnoses and transmits data about the patient’s condition.

No more panic, fear and adrenaline rush. Patient reviews testify to the absolute comfort of the procedure. The patient perceives the session as one minute when he takes a comfortable position and realizes that the procedure has already been completed.

Get advice from our specialists and sign up for the procedure at a convenient time for you.

90,000 General Anesthesia – What Happens and How to Prepare | Publications

Features of the procedure for general anesthesia

During the application of anesthesia, the anesthesiologist gradually plunges the person into a deep sleep, in which the patient is unconscious.

When immersed in anesthesia, the patient goes through three stages:

• Analgesia .At this stage, sensitivity decreases, diction is impaired. The specialist can only carry out simple, not provoking acute pain, operations.
• Excitation of the nervous system . The stage at which the pulse quickens, the heartbeat noticeably accelerates, a slight respiratory arrhythmia appears, the tone in the muscles increases, and pupil dilation is observed.
• Surgical stage . At this stage, the person is in a state of deep sleep, there is no susceptibility to pain of any level of intensity.

The involvement of a qualified anesthesiologist in the procedure under general anesthesia is a prerequisite in world practice.

Preparation for the general anesthesia procedure

Our task is to provide you with complete safety and comfort during surgery, research or treatment. A specialist anesthesiologist should be consulted prior to the procedure.

Our doctors will carefully study your situation: the presence of chronic and infectious diseases, allergies, recent vaccinations and pregnancy, and, if necessary, will send you for additional examinations, which can be passed in each of our clinics in Sergiev Posad, Khotkovo, Pushkino and Korolev.If there are no contraindications to the use of general anesthesia, the doctor will tell you about the specifics of preparing for the procedure.

It is strongly recommended to limit the intake of food and liquids 6 hours before the application of general anesthesia.

Observance of the doctor’s recommendations will allow specialists to carry out the anesthesia procedure and the operation in the most comfortable way for you. After treatment, you will be under the supervision of our highly qualified specialists for two hours.

Is anesthesia harmful?

In the medical community, it is believed that the use of modern anesthetics (namely, they are used in the Network of Family Polyclinics) is one of the safest types of anesthesia (in comparison, for example, with spinal or epidural anesthesia). To make the patient’s entry into anesthesia and awakening comfortable, doctors use combined anesthesia. Such anesthesia includes, for example, nitrous oxide and propofol, which eliminates the likelihood of side effects and has fewer contraindications.

Dreams during anesthesia

If you are a patient preparing for anesthesia, you are probably worried about what will happen to you during anesthesia. Will you see hallucinations, nightmares or lights at the end of the tunnel?

We dare to dissuade you. The anesthesiologists of the Family Polyclinics Network, with more than 29 years of experience, claim that when using general anesthesia with the use of modern anesthetics, patients, as a rule, have pleasant dreams, and the process of awakening from anesthesia does not cause headaches and other side effects.The main thing is to come to the doctor in peace and without unnecessary fears, and the doctor will do the rest for you.

90,000 Nitrous oxide (laughing gas) general anesthesia versus non-nitrous general anesthesia

Review question

We reviewed the evidence on the harmful effects of nitrous oxide on people undergoing general anesthesia (anesthesia).

Relevance

Nitrous oxide is an anesthetic gas that has been used for over 160 years to induce anesthesia and maintain anesthesia throughout the operation.It is also known as laughing gas. It is a colorless non-flammable gas with a pleasant, slightly sweet smell and taste. Its cheapness and low toxicity have made nitrous oxide the most commonly used agent for general anesthesia (anesthesia) today. However, some studies have shown that nitric oxide supplementation can be detrimental. This has prompted many anesthesiologists to ask about its further routine use in various operating conditions.

We wanted to find out if using nitrous oxide for general anesthesia was actually better or worse than not using it.

Characteristics of research

We reviewed the evidence as of October 17, 2014. We included 35 trials with a total of 13,872 adult participants who were randomized to receive nitrous oxide or no nitrous oxide. The trials covered various situations during general anesthesia.

Key Findings

We found that general nitrous oxide anesthesia increased the risk of pulmonary atelectasis (i.e.(i.e., the inability of the lungs to fully expand). When we limited our results to only the highest quality studies, we found that nitrous oxide could potentially increase the risk of pneumonia, severe nausea and vomiting. However, nitrous oxide had no effect on patient survival, the incidence of myocardial infarction, stroke, wound infection, blood clots in the veins, length of hospital stay, or length of ICU stay.

Quality of evidence

The evidence related to the survival of the participants was of moderate quality as we did not have enough data. The evidence for some of the harmful effects, inability of the lungs to fully expand and for heart attacks, was of high quality, while the evidence for other harmful effects, such as stroke and blood clots in the veins, was of moderate quality. For other outcomes, such as pneumonia, severe nausea and vomiting, and wound infection, the evidence was low-quality.The evidence related to long hospital stays was of moderate quality.

Authors’ conclusions

Avoiding nitrous oxide may be prudent for participants with pre-existing insufficient lung function or a high risk of postoperative nausea and vomiting.