After effects of propofol

Contents

Propofol

Generic Name: propofol (PROE poe fol)
Brand Names: Diprivan, Propoven

Medically reviewed by Kaci Durbin, MD Last updated on Feb 12, 2019.

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
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What is propofol?

Propofol (Diprivan) slows the activity of your brain and nervous system.

Propofol is used to put you to sleep and keep you asleep during general anesthesia for surgery or other medical procedures. It is used in adults as well as children 2 months and older.

Propofol is also used to sedate a patient who is under critical care and needs a mechanical ventilator (breathing machine).

Important information

Before you receive propofol, tell your doctor about all your medical conditions and allergies. Also make sure your doctor knows if you are pregnant or breast-feeding. In some cases, you may not be able to use propofol.

The FDA cautions recommends against using propofol if you are allergic to eggs, egg products, soybeans, or soy products.

Before receiving this medicine

You should not receive propofol if you are allergic to it. Tell your doctor if you have allergies to eggs, egg products, soybeans, or soy products.

To make sure this medicine is safe for you, tell your doctor if you have:

  • epilepsy or other seizure disorder; or

  • high cholesterol or triglycerides (a type of fat in the blood); or

  • liver or kidney disease.

Anesthesia medicine may affect brain development in a child under 3, or an unborn baby whose mother receives this medicine during late pregnancy. These effects may be more likely when the anesthesia is used for 3 hours or longer, or used for repeated procedures. Effects on brain development could cause learning or behavior problems later in life.

Negative brain effects from anesthesia have been seen in animal studies. However, studies in human children receiving single short uses of anesthesia have not shown a likely effect on behavior or learning. More research is needed.

In some cases, your doctor may decide to postpone a surgery or procedure based on these risks. Treatment may not be delayed in the case of life-threatening conditions, medical emergencies, or surgery needed to correct certain birth defects.

Ask your doctor for information about all medicines that will be used during your surgery or procedure. Also ask how long the procedure will last.

Propofol can pass into breast milk and may harm a nursing baby. However, as propofol acts and leaves the body quickly, most women can resume breastfeeding as soon as they are recovered from anesthesia and fully awake.

How is propofol given?

Propofol is injected into a vein through an IV. A healthcare provider will give you this injection.

You will relax and fall asleep very quickly after propofol is injected.

Your breathing, blood pressure, oxygen levels, kidney function, and other vital signs will be watched closely while you are under the effects of propofol.

What happens if I miss a dose?

Since propofol is given by a healthcare professional in a medical setting, you are not likely to miss a dose.

What happens if I overdose?

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

What should I avoid after receiving propofol?

Propofol causes severe drowsiness and dizziness, which may last for several hours. You will need someone to drive you home after your surgery or procedure. Do not drive yourself or do anything that requires you to be awake and alert for at least 24 hours after you have been treated with propofol.

Propofol side effects

Get emergency medical help if you have any signs of an allergic reaction to propofol: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Long-term use of propofol can lead to a syndrome called Propfol Infusion Syndrome, which may result in death.

Tell your caregiver right away if you have:

  • a light-headed feeling (like you might pass out) even after feeling awake;

  • weak or shallow breathing; or

  • severe pain or discomfort where the injection is given.

Common propofol side effects may include:

  • mild itching or rash;

  • fast or slow heart rate; or

  • slight burning or stinging around the IV needle.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect propofol?

Taking other medicines that make you sleepy or slow your breathing can worsen these effects. After you have been treated with propofol, ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures (especially valproic acid).

Other drugs may interact with this medicine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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Other brands: Diprivan, Propoven

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Related treatment guides

  • Anesthesia

Propofol Injection

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 mL of white, oil in water emulsion contains 10 mg propofol for IV administration. Nonmedicinal ingredients: soybean oil, glycerin, egg phosphatide, 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 in case needed.

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.

It is important that this medication be given exactly as recommended by your doctor. If you miss an appointment to receive propofol, contact your doctor as soon as possible to reschedule your appointment.

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
  • are planning to drive or operate any tools or machinery on the day of surgery
  • are pregnant or breastfeeding
  • have any contraindications to sedation or general anaesthesia
  • have high fat levels in the blood (high triglycerides)

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
  • difficulty breathing
  • dizziness
  • flushing
  • headache
  • heat or pain at the injection site
  • irregular heartbeat
  • low blood pressure
  • nausea or vomiting
  • rash

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:

  • agitation
  • cough
  • muscle spasms

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

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?

HEALTH CANADA ADVISORY

December 22, 2017

Health Canada has issued new restrictions concerning the use of Diprivan® (propofol). To read the full Health Canada Advisory, visit Health Canada’s web site at healthycanadians.gc.ca.

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: 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: This medication should not be used during pregnancy. 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. 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:

  • benzodiazepines (e.g., clonazepam, diazepam, lorazepam)
  • cyclosporine
  • inhaled anesthetics
  • medications that affect the muscles (e.g., neostigmine, suxamethonium)
  • miconazole
  • opioid pain relievers (e.g., codeine, fentanyl, morphine)
  • other medications that cause drowsiness
  • thiotepa

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 – 2020. 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/Propofol-Injection

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.

SIDE EFFECTS

General

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia And MAC Sedation In Adults

The following estimates of adverse events for propofol injectable emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with propofol injectable emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with propofol during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Anesthesia In Pediatric Patients

Generally the adverse experience profile from reports of 506 propofol injectable emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with propofol injectable emulsion during anesthesia in adults (see Pediatric percentages below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

ICU Sedation In Adults

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% – Probably Causally Related

Anesthesia/MAC Sedation ICU Sedation
Cardiovascular: Bradycardia Arrhythmia Tachycardia Nodal Bradycardia
Hypotension* (see also CLINICAL PHARMACOLOGY) Decreased Cardiac Output
Central Nervous System: Movement* Hypotension 26%
Injection Site: Burning/Stinging or Pain, 17.6%
Metabolic/Nutritional: Hyperlipemia*
Respiratory: Apnea (see also CLINICAL PHARMACOLOGY) Respiratory Acidosis During Weaning*
Skin and Appendages: Rash
Pruritus
Events without an * or % had an incidence of 1% to 3%
*Incidence of events 3% to 10%
Incidence less than 1% – Probably Causally Related
Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Anaphylaxis/Anaphylactoid Reaction, Perinatal Disorder, , , , , , , , , ,
Cardiovascular: Premature Atrial Contractions, Syncope
Central Nervous System: Hypertonia/Dystonia, Paresthesia Agitation
Digestive: ,
Hemic/Lymphatic:
Injection Site: ,
Metabolic:
Musculoskeletal: Myalgia
Nervous: , , , ,
Respiratory: Wheezing, , , Decreased Lung Function
Skin and Appendages: Flushing, Pruritus
Special Senses: Amblyopia,
Urogenital: Cloudy Urine Green Urine
Incidence less than 1% – Causal Relationship Unknown
Anesthesia/MAC Sedation ICU Sedation
Body as a Whole: Asthenia, Awareness, Chest Pain, Extremities Pain, Fever, Increased Drug Fever, Sepsis, Trunk Pain, Whole Body Weakness
Cardiovascular: Effect, Neck Rigidity/Stiffness, Trunk Pain Arrhythmia, Atrial Fibrillation, Atrioventricular Heart Block, Bigeminy, Bleeding, Bundle Branch Block, Cardiac Arrest, ECG Abnormal, Edema, Extrasystole, Heart Block, Hypertension, Myocardial Infarction, Myocardial Ischemia, Premature Ventricular Contractions, ST Segment Depression, Supraventricular Tachycardia, Tachycardia, Ventricular Fibrillation Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac Arrest, Extrasystole, Right Heart Failure, Ventricular Tachycardia
Central Nervous System: Abnormal Dreams, Agitation, Amorous Behavior, Anxiety, Bucking/Jerking/Thrashing, Chills/Shivering/Clonic/Myoclonic Movement, Combativeness, Confusion, Delirium, Depression, Dizziness, Emotional Lability, Euphoria, Fatigue, Hallucinations, Headache, Hypotonia, Hysteria, Insomnia, Moaning, Neuropathy, Opisthotonos, Rigidity, Seizures, Somnolence, Tremor, Twitching Chills/Shivering, Intracranial Hypertension, Seizures, Somnolence, Thinking Abnormal
Digestive: Cramping, Diarrhea, Dry Mouth, Enlarged Parotid, Nausea, Swallowing, Vomiting Ileus, Liver Function Abnormal
Hematologic/Lymphatic: Coagulation Disorder, Leukocytosis
Injection Site: Hives/Itching, Phlebitis, Redness/Discoloration
Metabolic/Nutritional: Hyperkalemia, Hyperlipemia BUN Increased, Creatinine Increased, Dehydration, Hyperglycemia, Metabolic Acidosis, Osmolality Increased
Respiratory: Bronchospasm, Burning in Throat, Cough, Dyspnea, Hiccough, Hyperventilation, Hypoventilation, Hypoxia, Laryngospasm, Pharyngitis, Sneezing, Tachypnea, Upper Airway Obstruction Hypoxia
Skin and Appendages: Conjunctival Hyperemia, Diaphoresis, Urticaria Rash
Special Senses: Diplopia, Ear Pain, Eye Pain, Nystagmus, Taste Perversion, Tinnitus
Urogenital: Oliguria, Urine Retention Kidney Failure

Read the entire FDA prescribing information for Propofol (Propofol Injectable Emulsion)

The remarkable memory effects of propofol

Not so long ago, the tried and true amnesic drug was diazepam, which was quickly replaced by midazolam when it became available. These drugs are often referred to as ‘prototypical benzodiazepines’, and the prototypical effect of greatest interest is well described by Sebel.1 He recounts the ability to eat dinner and have a conversation after a somnolent dose of ‘a benzodiazepine’, with no recollection of any bit of that transatlantic dinner the next day. This remarkable ability to wipe out episodic memory has been put to sinister use in the case of Rohypnol (flunitrazepam), which now has the unfortunate label of a ‘prototypical date-rape’ drug.2 It is an amazing state of affairs when a person can behave in essentially a normal fashion, yet have no recollection of any action, even traumatic ones, during this time period. Now it can be said that propofol is on the list of prototypical amnesic drugs.

In this issue of the BJA, Russell 3 has clearly described a situation of preserved conscious awareness and ability to follow complex commands with little or no recollection of these events after the fact. He has also shown that this most interesting situation cannot be identified using a Narcotrend brain monitor (more precisely, whether the brain is awake or asleep cannot be identified). Quite conceivably, this could also be true for other depth of anaesthesia (brain function) monitors in current use. As Russell states: ‘To date, no anesthesia brain monitor has been adequately validated in the presence of muscle relaxants for the duration of surgery with reference to individual patients’.

Nordstrom and Sandin4 have reported a similar effect on memory during propofol administration in the clinical setting. In fact, anaesthesia practice crucially depends on the production of a state of awareness and ability to follow commands without recollection of potentially traumatic situations later. This strange state of affairs is induced for procedures such as awake intubation and intra-operative ‘wake-up’ tests. Many practitioners remember an experience of a patient opening their eyes and looking at them when they should have been fully asleep! A typical response in such a situation is to give a sizeable dose of a readily available sedative/hypnotic drug. The nervous practitioner was then reassured when no memory of this event was present at the post-operative visit. Such experiences may lead to the false impression that a large dose of an amnesic drug will wipe out memory before the drug is given—the much sought after retrograde memory effect. Such an effect has never been demonstrated in humans. In reality, ongoing anterograde amnesia was present as the declining amount of anaesthetic drug had reached a sedative concentration. In fact, if anything, sleep after an experience will improve memory of it.5

Anecdotal and measured observations of amnesia with propofol lead to the question of what is it that we want to do? Though Russell focuses on the specific question whether consciousness is present, his descriptions of memory, or more correctly, the lack thereof for intraoperative events are very relevant. The important fact is that conscious awareness during surgery with muscle relaxation does not equate with horrible accounts of intra-operative awareness (the continuing low incidence of which is the focus of so much of the specialty’s and the public’s attention). The use of propofol as an amnesic drug has become possible because it can be given as a controlled i.v. infusion. Amnesia is present, as long as the pump functions correctly.6 Otherwise, it redistributes so quickly that periods of low drug concentration can easily occur, and then memory of events is possible.7 Falling drug concentrations at the end of the procedure likely account for the instances of memory reported by Russell. Yet, these recollections do not seem at all unpleasant—a dog walking on your stomach is quite different than being buried alive. It is interesting that the recollections reported by Russell are those that may be considered salient—‘this is Dr Russell…’, or a good dream about a daughter, as opposed to ‘green pear’. The brain does indeed respond more to personally relevant information, as measured by fMRI imaging during sleep.8

Thus, as we understand pharmacology and physiology better, and have better tools such as target controlled infusion pumps and monitors that measure the brain’s response to these drugs, do we need to aim for a continuous state of unconsciousness? It will be a brave new world when we can tell a patient undergoing a breast biopsy ‘don’t worry—you won’t remember this’ with confidence, rather than dialling up the propofol until they are snoring away. Russell makes the excellent point that we need to predict response in a given individual. Probabilities do not mean much when it is you at the end of the i.v. tubing. How your neighbour fared in a similar situation matters little at such a time. The way to individual predictability is understanding how amnesic drugs work in the brain and then developing a monitor to measure this effect.

What is known about how propofol produces its amnesic effect? The translation of observations of Russell, and Nordstrom and Sandin into measurable responses that can inform us of mechanisms of drug action on memory is a difficult one. Using memory paradigms such as a continuous recognition task, or deep vs shallow processing, we have shown that information is encoded into long-term memory in the presence of propofol. However, this information is then forgotten over time.9 Looking at task related changes in regional cerebral blood flow, there is preliminary evidence that the brain’s response to encoding of new information is normal in the presence of propofol, even when this information is then later forgotten.10 These findings make sense of observations such as Sebel’s transatlantic dinner. But, as with Churchill’s Russia, why the brain forgets what it has learned when an amnesic drug is present is still a riddle wrapped in a mystery inside an enigma.

Russell has described what could be a ‘gold-standard’ for critical testing of depth of anaesthesia (brain function) monitors. The realization that, in itself, being aware but having no memory of the episode is not a traumatic event allows ethical research to be done in the setting of the surgical procedure itself. As most brain function monitors have been developed using surrogate measures, such as responsiveness during induction of anaesthesia or in volunteer studies, or by explicit recall after surgery, it is unclear how other monitors would fare in Russell’s operating theatre.

Also unclear is the influence of the combination of epidural or spinal anesthesia with a general anesthetic on the ability to remember stimuli. It has been well demonstrated that negative stimuli are remembered better than pleasant ones, secondary to hormonal responses affecting the amygdala, which in turns affects the ability to remember events.11 This differentiation is exaggerated at sedative concentrations with certain drugs.12 Such modulatory influences on memory formation during anaesthesia is a question of current interest.1314 On the other hand, spinal or epidural anaesthesia, and possibly drugs such as dexmedetomidine, may be expected to blunt hormonal responses and diminish influences of the amygdala on memory formation, as is the case with beta blockers.15 Thus, memory for events in Russell’s paradigm may be greater without epidural blockade, as responsiveness of the brain is influenced by the spinal cord.16

A welcome portion of Russell’s study is data on the ease of use of the Narcotrend monitor in a clinical situation. The information about time required and the number of electrodes needed to get the system working or the time the screen was blank during the case is very helpful and is reminiscent of my own experiences with various brain function monitors. It is a hopeful transition to see studies not only examine important scientific questions but ones important to the practising clinician as well.

Based on Russell’s keen observations, one can state that the Narcotrend monitor cannot reliably detect the transition from consciousness to unconsciousness in individual cases. However, this statement needs to be tempered with the fact that no depth of anaesthesia monitor may be able to do this in Russell’s setting. I have no doubt that monitors can be refined to work well in Russell’s paradigm, but then the question is whether we want a monitor to detect unconsciousness or one that detects amnesia?

1 Sebel PS. Memory during anesthesia: gone but not forgotten? Anesth Analg 1995; 81 : 668–70 2 Schwartz RH, Milteer R, LeBeau MA. Drug-facilitated sexual assault (‘date rape’). South Med J 2000; 93 : 558–61 3 Russell IF. The Narcotrend ‘depth of anaesthesia’ monitor cannot reliably detect consciousness during general anaesthesia: an investigation using the isolated forearm technique. Br J Anaesth 2006; 96 : 346–52 4 Nordstrom O, Sandin R. Recall during intermittent propofol anaesthesia. Br J Anaesth 1996; 76 : 699–701 5 Gais S, Born J. Declarative memory consolidation: mechanisms acting during human sleep. Learn Mem 2004; 11 : 679–85 6 Mathews DM, Rahman SS, Cirullo PM, Malik RJ. Increases in bispectral index lead to interventions that prevent possible intraoperative awareness. Br J Anaesth 2006; in press 7 Glass PS. Prevention of awareness during total intravenous anesthesia . Anesthesiology 1993; 78 : 399–400 8 Portas CM, Krakow K, Allen P, et al. Auditory processing across the sleep–wake cycle: simultaneous EEG and fMRI monitoring in humans. Neuron 2000; 28 : 991–9 9 Veselis RA, Reinsel RA, Feshchenko VA, Johnson R Jr. Information loss over time defines the memory defect of propofol: a comparative response with thiopental and dexmedetomidine. Anesthesiology 2004; 101 : 831–41 10 Veselis RA, Pryor KO, Reinsel RA, et al. The amnesic effect of propofol occurs after normal encoding: an O-15 PET study using thiopental and propofol (abstract). Neuroimage 2005; 26 : A759 11 Cahill L. The neurobiology of emotionally influenced memory. Implications for understanding traumatic memory. Ann N Y Acad Sci 1997; 821 : 238–46 12 Pryor KO, Veselis RA, Reinsel RA, Feshchenko VA. Enhanced visual memory effect for negative versus positive emotional content is potentiated at sub-anaesthetic concentrations of thiopental. Br J Anaesth 2004; 93 : 348–55 13 Deeprose C, Andrade J, Harrison D, Edwards N. Unconscious auditory priming during surgery with propofol and nitrous oxide anaesthesia: a replication. Br J Anaesth 2005; 94 : 57–62 14 Deeprose C, Andrade J, Varma S, Edwards N. Unconscious learning during surgery with propofol anaesthesia. Br J Anaesth 2004; 92 : 171–7 15 Strange BA, Dolan RJ. Beta-adrenergic modulation of emotional memory-evoked human amygdala and hippocampal responses. Proc Natl Acad Sci USA 2004; 101 : 11454–8 16 Antognini JF, Jinks SL, Atherley R, Clayton C, Carstens E. Spinal anaesthesia indirectly depresses cortical activity associated with electrical stimulation of the reticular formation. Br J Anaesth 2003; 91 : 233–8 © The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: [email protected]

Propofol Induces Postoperative Depression and Inhibits Microglial Function in Mice

Abstract

Many patients experience excellent physical recoveries after surgery; however, there are some of them who from suffer mood fluctuation, even depression. Postoperative depression may be resulted from cognitive dysfunction, pain, and a compromised immune system during the surgery. But there is a higher possibility that general anaesthesia may be responsible for the development of depression. Here, we employed one of the most used anaesthetics, propofol, in a mouse model to investigate whether this intravenous anaesthetic compound could cause depressive-like behavioural performance in mice. We found a single dose of propofol caused significant abnormal behavioural performance in tail suspension, forced swimming, and open field tests. We also examined the brain section of these mice and revealed that there was significant reduced expression of the CD11b protein, which demonstrated an inhibition of propofol on microglial function. We investigated the effect of propofol on synaptic protein, SYP, and found there was no notable influence on the protein expression. These above results suggested that propofol treatment might promote the depressive-like behaviours in mice via influencing the microglial cell function. Furthermore, we found the level of the IL-6 cytokine was significantly increased in the brain tissue, which might subsequently cause the activation of the transcriptional factor, STAT3. Our finding may provide a new perspective of further understanding the mechanism of anaesthetic drugs and deciphering the underlying mechanism of postoperative depression.

1. Introduction

Many patients who undergo general anaesthesia or surgery experience some form of postsurgical depression, especially during the six months following an invasive procedure . As one of the frequent complications after surgery, depression may lead to further morbidity and mortality, especially for elderly patients . Meanwhile, researchers have discovered that depressed patients are more likely to have other complications after surgery . They are less able to cooperate well with the caregivers in their after-surgery care, such as rehabilitative therapy. In patients who already have a preexisting depression or anxiety history, the recovery time from postsurgical depression is much longer . A study also suggested surgery might exacerbate the severity of the preexisting depression . So far, little is known about why there is such a strong link between surgery and depression. Some researchers have thought the psychological reason per se is that many people experience postsurgical depression because the surgical procedures force them to confront their own mortality. Some studies also emphasized the specific types of surgery per se on the induction of postsurgical depression since depression seems to be more often observed in some major surgeries, including brain surgery, hip replacement surgery, and cancer resection. However, recent studies suggested that the length of time spent under anaesthesia seemed to be related to the likelihood and severity of depression . Propofol is one of the most used anaesthetics in the intensive care setting after surgery . Propofol treatment has been found to be significantly associated with cognitive dysfunctions in the postoperative period . There is no effort made to examine whether and how propofol could impact the mood status in patients and animals so far. Therefore, we employed a mouse model with a single dose of propofol treatment and tested the depressive-like behaviours in the mouse model. We found mice exposed to a single dose of propofol treatment exerted anxiety-like behaviours in an open field test by showing less time in the center area and depressive-like behaviours in tail suspension and forced swimming tests by showing longer immobility time than control mice without injection of propofol. Our results indicated that propofol might be responsible for the mood fluctuation after surgery and this effect may be associated with the influence of propofol on the microglia cells in the central nervous system (CNS).

2. Materials and Methods

2.1. Animals and Drug Treatment

In the present study, we used 8-10 weeks old male C57BL/6 mice. All mice were free to access water and food. For all the animal studies here, mice were treated strictly following the guidelines established by the Chinese Council on Animal Care. All the procedures were approved by the Animal Care Committee of Qingdao Municipal Hospital, Shandong, China. There were two groups of mice in the study: normal saline (controls; ) and propofol (75 mg/kg; ). A single-dose injection of propofol was administrated to the mice intraperitoneally. Commercial propofol injection solution (Xi’an Libang Pharmaceuticals, China) was used here. The dose of propofol used here is adapted from the previous study . During the anaesthesia time, all mice were put on the heating pad to maintain their body temperature. Behavioural tests were performed 1 week later.

2.2. Open Field

A square wood box was used here for the open field test as previously described . At the beginning of the test, each mouse was placed in a corner of the box facing the wall. The total traveled distance and total time spent in the inner squares of all mice were recorded and measured in a 5-minute session.

2.3. Tail Suspension Test

For the tail suspension test, the procedures were performed as previously reported . Mice were suspended through tails with a tape on a small metal hook, and they cannot escape or hold on to nearby surfaces in this position. The total time the mice spent immobile during the 6 min testing period was recorded. Immobility is defined as a lack of attempt of mice to move their bodies.

2.4. Forced Swimming Test

We carried out the forced swimming test as previously reported . Mice were placed in a glass beaker filled with water at room temperature. We tested the total immobile time of mice in a 15 min testing session, and the last 6 min was scored for immobility duration. At the end of each test, the wet mice were immediately placed in a cage with normal bedding after they were warmed up in a dry towel.

2.5. Elevated Plus Maze Test

The elevated plus maze is a simple method for evaluating animal anxiety responses. We tested the anxiety level of mice by using the elevated plus maze assay as previously reported . Basically, the elevated plus maze apparatus is equipped with two open and two closed arms and elevated to a height of around 50 cm above the ground. At the beginning of each test, the mouse was placed in the central square by facing the open arm and then was allowed to explore the arms for 5 min. The amount of time spent in the open arms was recorded and analyzed by a person who was not involved in the experimental design.

2.6. Enzyme-Linked Immunosorbent Assay (ELISA)

We measured the IL-6 level in brain tissues by using a commercial ELISA kit (eBioscience, Thermo Fisher Scientific). Each sample was assayed in a duplicate manner with appropriate dilutions in order that relative luminescent units could fall within the linear range of standard curves. The value of IL-6 from each sample was normalized and expressed as a ratio compared to the total loading protein as a relative ratio. The absorbance of each sample was measured with a microplate reader (Synergy Mx, BioTek, Winooski, VT).

2.7. Western Blot

Dissolved brain samples were processed and run on SDS-PAGE gels. They were then transferred onto PVDF membranes that were then blocked with 5% skim milk in TBST buffer. The blocked membranes were further investigated with antibodies to CD11b (1 : 4000; Abcam, UK), synaptophysin (SYP), p-Stat-3 (1 : 1000; Cell Signaling, Danvers, MA), and total Stat-3 (1 : 1000; Cell Signaling, Danvers, MA) in TBST milk overnight at 4°C. After incubation with the secondary antibodies for 2 hours at room temperature respectively, the bands of protein on the membrane were disclosed with chemiluminescence reaction. β-Actin was used as an internal control (1 : 5000; Santa Cruz Biotechnology, CA, USA). Quantitative results were expressed as a ratio of each target protein to its β-actin.

2.8. Statistical Analysis

Values presented in the study were shown as the . The significance of difference between two groups was determined by Student’s -test analysis. A value of less than 0.05 was regarded as statistically significant.

3. Results

3.1. Single Dose of Propofol Exposure Caused Depressive-Like Behaviours in Mice with Tail Suspension and Forced Swimming Tests

Firstly, we tested the hypothesis whether a single dose of propofol treatment could cause long-term effects on the behavioural performance in mice by focusing on the depression manner. We employed the tail suspension and forced swimming tests in these mice to explore the long-term effects of propofol. In the tail suspension test, we found propofol significantly increased the immobile time compared to the control mice without propofol treatment when the mice were hanged in tails (Figure 1). To further confirm the depressive-like behaviours in the mice exposed to propofol, we used the force swimming method to measure the immobile time of these mice. Our results demonstrated that propofol increased the total time of immobile time compared to mice in the control group (Figure 2). These above findings revealed that a single dose of propofol treatment could cause and sustain the long-term depressive behavioural performance in mice.

Figure 1 Propofol increased the total immobile time of mice compared to control mice in the tail suspension test. All data are expressed as the . . .
Figure 2 Propofol increased the total immobile time of mice compared to control mice in the forced swimming test. All data are expressed as the . . .

3.2. Single Dose of Propofol Exposure Caused Anxiety-Like Behaviours in Mice with Open Field and Elevated Plus Maze Tests

Anxiety is the highest cooccurrence complication in depression. Therefore, we postulated whether propofol could induce anxiety-like behaviours in these mice, basing on the above behavioural results in these mice. We used the open field assay to test the anxiety level of these mice. As shown in Figure 3(a), propofol treatment effectively reduced the total time mice spent on the center area in the open field. And we also measured another important parameter of the test, the total travel distance of the mice. As we expected, propofol injection significantly decreased the travel distance of mice in the 5 min test session compared to control mice (Figure 3(b)). Next, we investigated the anxiety-like behaviours of these mice in elevated plus maze assay. We found that mice exposed to propofol showed significant less time spent in open arms (Figure 4), which was in line with the results from the open field test.

(a)
(b)
(a)
(b) Figure 3 Propofol caused anxiety-like behaviours of mice in the open field test. (a) Propofol decreased the total time in the center area of mice compared to control mice in the open field test. (b) Propofol decreased the total travel distance of mice compared to control mice in the open field test. All data are expressed as the . . .
Figure 4 Propofol decreased the total time in the open arms of mice compared to control mice in the elevated plus maze test. All data are expressed as the . . .

3.3. Single Dose of Propofol Exposure Caused the Increased Level of IL-6 in the Brain Tissues of Mice

A recent study suggested the involvement of neuroinflammation in postoperative delirium-like cognitive deficits . We tested whether propofol could impact the expression level of IL-6 in the brain tissues of these mice. To achieve the conclusion, we performed ELISA assay in the brain tissues (hippocampus and cortex) to assess the level of IL-6 in mice with or without propofol treatment. Our results demonstrated that propofol treatment in this condition could be able to upregulate the expression level of this cytokine in the brains of mice exposed to propofol (Figure 5). This result indicated that propofol might cause the anxiety- and depressive-like behaviours in mice by affecting the inflammatory response in their brains.

Figure 5 Propofol increased the IL-6 level in the brain tissues of mice compared to control mice. All data are expressed as the . . .

3.4. Single Dose of Propofol Exposure Caused the Reduced Expression of CD11b and Increased Expression of p-STAT-3 in the Brain Tissues of Mice

Last, we probed the possible cellular and molecular mechanisms that might be responsible for the behavioural changes in these mice exposed to propofol. We tested whether glial cells were influenced by the propofol treatment by looking at the microglial maker protein, CD11b. With a western blot study, we found the expression level of CD11b was reduced in the brains of mice with propofol treatment (Figure 6(a)), which suggested that microglial function might be regulated by the propofol treatment. Meanwhile, the expression of the presynaptic protein SYP was not affected by the propofol treatment (Figure 6(c)). We also studied the function of the transcriptional factor STAT-3 by investigating the phosphorylation status of STAT-3 (p-STAT-3). Our western blot results demonstrated that propofol treatment caused the increased expression level of p-STAT-3 without affecting the expression of total STAT-3 (Figure 6(b)). These findings implicated that propofol might influence the microglial cell function and enhance the phosphorylation of STAT-3 while inducing the anxiety- and depressive-like behavioural performances in mice.

(a)
(b)
(c)
(a)
(b)
(c) Figure 6 Propofol influenced the function of astrocytes and STAT-3 in the brain tissues of mice compared to control mice. (a) Propofol decreased the expression of the CD11b protein in the brain of mice. (b) Propofol increased the expression of the p-STAT-3 protein in the brain of mice. (c) Propofol did not change the expression of the SYP protein in the brain of mice. All data are expressed as the . . .

4. Discussion

Cognitive and memory dysfunctions have been fairly studied, but the postoperative mood fluctuation has not attracted enough attention so far. Some evidences supported the idea that there were significant mood changes that occurred in the patients who are exposed to surgery and anaesthetic treatment. Here, we tested a new hypothesis that anaesthetic treatment per se may be enough to significantly affect the mood status in animals that underwent the single dose of anaesthetic treatment without an accompanying surgical procedure. We used propofol as the representative anaesthetic compound and intraperitoneally injected it to the mice. In the following days, a series of depressive and anxiety behaviours were performed to observe the mood changes in the mice. We found that there were significant differences on the behavioural performances between these mice with or without propofol exposure. Since these propofol-induced effects were sustained for a significant time while even after the medication was took off, we postulated that these effects were not the acute anaesthetic influence but were mediated by other systems in the CNS.

Neuroinflammation has been found to be one of the major factors that contribute to the depression and other mood changes in the CNS . Here, we asked whether a microglial cell was activated in the brain of mice after propofol exposure. The microglial cell protein marker, CD11b that is one of the common marker proteins to demonstrate the activation of microglia, was investigated with western blot. Surprisingly, our results indicated that propofol could inhibit the protein level of CD11b. The plausible explanation here is propofol could inhibit the CD11b protein expression regardless of whether the microglial cells were activated or not. The prominent advancement of propofol may be important for the potential treatment of alleviating the microglial overactivation in some pathological conditions of the CNS, such as trauma, stroke, and multiple sclerosis. We also looked into the effect of propofol on the synaptic proteins that are very important fundamental factors behind the behavioural performances of animals . Interestingly, although propofol could affect the microglial cell function, it seemed not to impact the synaptic protein expression level. These findings are not in line with some previous reports . The possible reason may be due to the difference of time window when the proteins were collected after the propofol was given. But our findings still suggested that propofol might have a different impact on neuron and other glial cells. In the future study, the effects of propofol on glial and neuronal cells should be elaborated individually.

The neuroinflammatory response in the CNS exposed to the single dose of propofol was further validated by the ELISA test of IL-6 in these two groups of mice. We found propofol treatment could induce an upregulation of IL-6 in the mouse brain. These findings were in line with the results of propofol on the microglial cell function. While inhibiting the CD11b component, propofol may activate the relevant signaling pathways that are important for the microglial cell activation.

Collectively, our study suggested propofol was able to influence the microglial cell function and exacerbate inflammatory response in the CNS. The cellular and molecular reaction might be responsible for the behavioural changes in these mice that are administrated with the single dose of propofol. Our study emphasized the important role of anaesthetics on the impact of mood changes after operation, but mood could be significantly impacted by many factors, including inflammation that is quite often seen in the patients during and after surgery. Therefore, a series of well-designed, systemic studies on an animal model which involved not only the anaesthetics but also the surgery procedure are warranted for the future.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

All the authors declare that they have no conflicts of interest.

Acknowledgments

The authors thank the funding support from the Department of Orthopedics, Qingdao Municipal Hospital, Qingdao, Shandong, China, and the technical support from Weifang Medical University, Weifang, China.

In the first week of the trial of Conrad Murray, Michael Jackson’s physician, Los Angeles jurors heard audio recordings of the late pop star’s slurred speech, in addition to the litany of prescription drugs he had taken in the hours and weeks prior to his June 25, 2009, death.
It will be up to them to decide if they agree with the Los Angeles County coroner’s office, which labeled Jackson’s death a homicide.
According to the 2009 autopsy report (pdf), “the cause of death is acute propofol intoxication,” which caused the singer to stop breathing. In addition to propofol (a hypnotic drug used for general anesthesia, sedation and in veterinary medicine) the examiner also found traces of lorazepam (a benzodiazepine drug used to treat anxiety and insomnia); midazolam (another benzodiazepine, indicated for insomnia and medical sedation); lidocaine (a local anesthetic often included with propofol to relieve injection pain); diazepam (a benzodiazepine to treat anxiety, insomnia and alcohol withdrawal); and nordiazepam (a benzodiazepine-derived sedative, often used to treat anxiety) in Jackson’s bloodstream.
To support the weighty pronouncement of homicide, the medical examiner concluded that: “circumstances indicate that propofol and the benzodiazepines were administered by another. The propofol was administered in a nonhospital setting without any appropriate medical indication. The standard of care for administering porpofol was not met.”
Prosecutors are following this line of evidence, arguing that Murray should be held responsible for Jackson’s death because he lacked adequate justification, expertise and equipment for giving this powerful drug to his client (who was reportedly aiming to stay rested in preparation for a comeback tour). Although Murray was using a device to keep tabs on Jackson’s vitals, as is recommended while using a general anesthetic, the fingertip pulse and blood-oxygen monitor he used is “specifically labeled against continuous monitoring,” said an executive from Nonin Medical, Inc., which makes the $275 device, CNN reported Friday. And according to testimony from a paramedic that responded to the 911 call and found Jackson without a pulse, Murray did not mention giving Jackson anything other than the lorazepam.
Given Jackson’s apparently substantial admixture of meds and oft-discussed medical conditions, why was propofol the most likely candidate for his death—and can it be used more safely? To find out, Scientific American spoke with Beverly Philip, a professor of anesthesia at Harvard Medical School.

Propofol is not your run-of-the-mill sleeping aid. How does it differ from more commonly used sedatives?
It’s not a sleeping aid at all. What it is is a general anesthetic. This puts people into general anesthesia—a sleeping aid doesn’t do that.
This is not meant to be used at home. This is meant to be used by anesthesiologists in a clinical setting. So the use as a sleep aid is way off the mark.
How does propofol work in the body?
We don’t know exactly how general anesthesia works. This works as other general anesthetics work, acting on receptors in the brain—possibly the GABA receptors, because that is a mechanism for a lot of sleepiness in the brain.
Are there negative side effects that propofol can have—even when it is used as directed and in a proper setting?
Yes. Unlike other sedatives, this drug has an extraordinarily narrow safety margin. It changes the body’s state very rapidly so that the patient will go unconscious and stop breathing. It can affect the breathing even before unconsciousness. So even in trained hands, it is very difficult to titrate just where you want. We can do it, but that’s what we’re trained and educated to do—it’s not easy. If I’m inducing anesthesia, it will act inside of 60 seconds.
So as a cardiologist and personal physician to Michael Jackson, is it likely that Conrad Murray did not have the proper training to administer this type of drug safely?
I have heard nothing about how he had had training to use the drug. How it was used here, we call it recreational use. This had nothing to do with the medical care of a patient, which is a situation in which you have things to make it safe, so it’s not even in the ballpark of normal use.
The drug also has some reportedly pleasant side effects, such as euphoria. Is that common among sedatives?
When it first came out it was very obvious that it causes euphoria. It’s not that dissimilar to alcohol. It reduces inhibition, people get giddy, and whatever thoughts they have on their mind, they tell you. It can also cause hallucinations, because whatever is in a person’s head is more likely to be seen. We see it as they go off to sleep and as they wake up.
Recreationally, a lot of people die from this. It’s very difficult to administer safely even in the most controlled settings.
The FDA is in the process of making this a restricted drug, recognizing its euphoric property.
Are there other anesthetics that are used off-label as sleep aids?
There are other things that are quite in a different class. For example, Valium and its cousins: In very, very high doses, someone could sleep, but you have to give lots of it, and it works very slowly to cause sleep.
Drugs in the Valium class and painkillers have a reversing agent that’s commercially available. There’s no reversing agent for propofol.
The coroner’s reports from Michael Jackson’s autopsy also found evidence that he was on other drugs at the time he died, including lidocaine, lorazepam and diazepam. Is it possible Jackson’s death was due to a reaction from these drugs or do you think propofol alone could have killed him?
There’s quite a sufficient answer just with this drug alone. But as with any other intoxicant, when you’ve taken any other drug, they all add up—and propofol is no different.
The fact that there’s no reversing agent, and the ability to pull someone out of it—which we call rescuing—requires considerable professional training.
This is not a sleeping aid. This is a general anesthetic drug. Everyone has been saying, “Michael Jackson wanted to be asleep.” No one talked about relaxing drugs. With this drug in unskilled hands, this sleep was permanent. It induces general anesthesia, which is not like a night’s sleep.

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

10. Adverse Effects, Fatal Intoxications, and Autopsy Findings

Table 1 presents major adverse and side effects of propofol. The pronounced respiratory and cardiac depression are relevant adverse outcomes. There have been also reports of a PRIS occurring in approximately 1 in 300 patients when it has been given in high doses and for a prolonged period to maintain sedation, particularly critically ill patients in intensive care units and children . PRIS is characterized by severe metabolic acidosis, skeletal muscle necrosis (rhabdomyolysis), hyperkaliemia, lipaemia, hepatomegaly, renal failure, arrhythmia and cardiovascular failure, and death. The pathophysiology of PRIS appears to involve a disturbance of mitochondrial metabolism by affecting β-oxidation of free fatty acids .

The risk of death due to self-administered propofol has been debated and several authors reported it to be low or absent, namely, due to the low concentration found in commercial ampoules (20 ml contains 200 mg propofol) that is equivalent to a standard dose of 2–2.5 mg/kg body weight to a healthy 80 kg individual to induce general anesthesia within 1-2 min after injection and arousal after 5–10 min . Due to the fast-acting narcotic effect of propofol, the self-injection of more than one ampoule at a time is unlikely. However, victim can mix the content of one or more vials for rapid and continuous intravenous infusion and therefore administration will continue despite loss of consciousness . Another challenge that faces forensic toxicologists is the fact that in most case reports of fatal propofol abuse, blood concentrations were lower or within the commonly accepted therapeutic range (1–8 µg/mL) after a standard anesthetic induction dose . According to the short half-life, this may suggest that after losing consciousness, the victim probably survived enough time to reduce blood propofol level through distribution, metabolism, and excretion . Nevertheless, for results interpretation it is important to remember that therapeutic levels of propofol apply to an anesthetized patient with respiratory support which is lacking in reported propofol abuse cases and that there is a wide variability of propofol plasma concentrations . Moreover, propofol is also coabused with other drugs, namely, benzodiazepines, z-drugs, barbiturates, and opioids . Indeed, a synergistic interaction has been found with benzodiazepines at the receptors, such that the dose of propofol required to induce anesthesia should be reduced in the presence of midazolam .

One of the major drawbacks for the diagnosis of propofol forensic intoxications is the fact it is usually not included in standard drug screening analysis and, due to its low molecular weight and volatility, might be missed even in confirmatory exams. Although newer techniques are available for the direct detection of minute quantities of propofol in exhaled air of anesthetized patients , such approaches are not readily available in forensic institutions and therefore there is also a long field of opportunities to uncover abusive cases.

Autopsy and histological findings observed in lethal cases resulting from propofol overdose usually report cerebral and pulmonary edema, polyvisceral congestion, lungs with some petechial hemorrhages on pleural surface, hemorrhagic pancreatitis, and hepatic steatosis . Although claimed as very rare idiosyncratic reaction (<1/10,000) and with a an estimated incidence of 0.1%–2% of all pancreatitis cases, hypertriglyceridaemia has been suggested as a causal relationship between propofol and pancreatitis since it is formulated as a fat emulsion . Therefore, patients who develop hypertriglyceridaemia are at risk of developing pancreatitis, and serum triglyceride concentrations should be routinely monitored in these patients and alternative sedation strategies should be considered when hypertriglyceridemia is detected . Nevertheless, some case reports describe the development of propofol-induced acute pancreatitis in the absence of hypertriglyceridaemia .

11. Conclusion and Future Perspectives

Drugs with actions on the central nervous system are of particular importance in pharmacology, and major groups include anxiolytics, sedatives and hypnotics, antiepileptic, antipsychotics, antidepressant, antiparkinson, stimulants, general anesthetics, opioids, drugs for preventing or treating migraine, and miscellaneous drugs, including anticholinesterases, appetite suppressants, and centrally acting muscle relaxants. Other drugs may be administered to prevent or treat general pathologies to brain tissue (e.g., cytotoxic agents for tumors, antibiotics for infections, or anti-inflammatory agents in cerebral edema). Additionally, many drugs given for peripheral effects may cross the blood-brain barrier and have side effects on the central nervous system (e.g., autonomic drugs, antihistamines, and local anesthetics) and psychoactive illicit substances also exert central nervous system actions.

In this work, metabolism of propofol and respective genetic variability was fully reviewed. In humans, propofol produces inactive metabolites. It undergoes direct polymorphic O-glucuronidation in humans to propofol-glucuronide and hydroxylation to 2,6-diisopropyl-1,4-quinol. The latter substance subsequently undergoes phase II metabolism, resulting in the formation of further metabolites 4-(2,6-diisopropyl-1,4-quinol)-sulfate, 1- and 4-(2,6-diisopropyl-1,4)-glucuronides, or sulfates . Further minor phase I propofol metabolites such as 2-(ω-propanol)-6-isopropylphenol and 2-(ω-propanol)-6-isopropyl-1,4-quinol are also described. Propofol is excreted in the urine after glucuroconjugation of the parent drug (to form the propofol-glucuronide) and sulfo- and glucuroconjugation of the hydroxylated metabolite to form 4-(2,6-diisopropyl-1,4-quinol)-sulfate, 1- or 4-(2,6-diisopropyl-1,4)-glucuronide, respectively. Current evidence suggests that close monitoring is required when administering anesthetics to individuals with the CYP2B66 allele . Nevertheless, additional studies are needed to elucidate and characterize polymorphic enzymes in explaining interindividual variations of the glucuronidation metabolic pathway and their pharmacological and toxicological adverse reactions. Although positive pharmacogenetic polymorphic associations have been found with clinical significance, the lack of reproducibility is a limitation, since most studies focus on single variant associations, while interindividual differences in propofol metabolism may be best explained through the contribution of multiple pathways. Indeed, the narrow therapeutic index and significant variability in patients’ responses to anesthesia and surgery make the potential for severe adverse reactions high during the perioperative period. The identification of additional metabolites is also required to confirm xenobiotic exposure in a wider detection window, especially in alternative samples. Moreover, despite the fact that there are sex and racial/ethnic differences in response to propofol, to date, there is no strong evidence linking genetic variation to such observations, possibly due to the additional influence of weight, height, and lean body mass, environmental factors, and severe hepatic or renal impairment propofol pharmacokinetics . Equally important is the potential for variation at the site of propofol action. In vitro it was shown that Y444W variant attenuates the effect of propofol, but associations with receptor polymorphisms and clinical relevant effects of propofol need further studies . Sites on the β1-subunit (M 286), -subunit (M 286), and β3-subunit (N265) of the transmembrane domains are crucial for the hypnotic action of propofol . The -subunit and -subunit subtypes also seem to contribute to modulating the effects of propofol on the GABA receptor .

Finally, metabolomics of propofol was not yet extensively studied and further studies are needed to clarify whether the different metabolomic patterns are significant from the clinical point of view, namely, taking into account sex, age, genetic polymorphisms, and different pathologic conditions.

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

The author acknowledges Fundação para a Ciência e a Tecnologia (FCT) for his Investigator Grant (IF/01147/2013). This work was supported by FEDER under Program PT2020 (Project 007265 -UID/QUI/50006/2013).

Anesthesia Works… But Why?

People undergo anesthesia all the time during surgery. Even though being “put under” is quite common, there’s still plenty that doctors don’t know about it.

Having a better understanding of how anesthesia works could improve drugs used during the process.

That’s what Bruno van Swinderen, PhD, an associate professor from the University of Queensland in Australia, set out to do in a recent study published in Cell Reports.

He said his team has found that propofol, a common drug used in anesthesia — the one involved in Michael Jackson’s death — goes beyond simply putting a person to sleep.

“Propofol anesthesia is extremely safe, as is most general anesthesia today,” van Swinderen told Healthline. “However, knowing this alternate mechanism might help us understand why recovery from general anesthesia is slow and sometimes problematic. You can keep people under with propofol safely for a long time, so my feeling is that we’ve hit on a drug that works pretty well,” he noted.

“Propofol is the sedative of choice given to first knock you out. Usually, other anesthetics are then given to keep you under,” van Swinderen added.

How does it work?

What exactly does propofol do?

Van Swinderen’s team examined the impact of propofol on the synaptic release in rats. Synaptic release is how neurons or nerve cells communicate with each other.

Doctors had known propofol impacts the brain’s sleep system similar to a sleeping pill, but van Swinderen said his team discovered that it disturbs presynaptic mechanisms as well.

This probably affects communication between neurons throughout the brain in a way that’s different than being asleep.

“In this way, it is very different than a sleeping pill,” he said in a statement.

The researchers found that propofol restricted the movement of a key protein — syntaxin1A — that’s required at the synapses of all neurons. That lowers communication between brain neurons.

This could explain why patients typically are groggy after surgery, van Swinderen said.

“We think that widespread disruption to synaptic connectivity — the brain’s communication pathways — is what makes surgery possible, although effective anesthetics such as propofol do put you to sleep first,” he said.

The discovery could explain why general anesthesia can be problematic for younger and older patients, they said.

Difficulties with research

Van Swinderen said that the challenge in studying the response to anesthesia is to find out how countless small effects during the presynapse phase lead to major changes in how the brain works.

“That is difficult to study in humans,” he said. “It is also difficult to line up a super-resolution microscope onto cells in a human brain.”

There’s a great value in using animal models because the synaptic release infrastructure in animals and humans is almost identical. Humans just have more brain cells, he said.

A drug that provides better control of the immobilization (or remobilization) of syntaxin1A at the presynapse would give physicians better control of how and when to keep the brain unresponsive, van Swinderen said. If such drugs were developed, they could be used in combination with classical sedatives.

Complications and dangers

Long-term harms or complications of anesthesia aren’t well understood and are debated in the field.

“General anesthesia is extremely safe, but we just don’t know whether some of the complications result from this potentially brain-wide effect,” he said.

“Human brains have a trillion synapses,” van Swinderen explained. “If syntaxin1A mobility is impaired in each one, you could imagine how that might lead to lasting changes in the long run. But this is still just a hypothesis that needs to be tested.”

Waking up during surgery — something known as intraoperative awareness — is rare, according to James Lozada, DO, a fellow in obstetrical anesthesiology at the Northwestern University Feinberg School of Medicine in Illinois.

This occurs in 1 or 2 of about 1,000 procedures, according to The American Society of Anesthesiologists. Other reports state that 1 out of every 19,000 patients experiences intraoperative awareness during a procedure.

Lozada said it can be more common in procedures when the patient is unstable such as trauma-related surgeries, emergency cesarean section operations, or those that require lower doses of medication to safely treat the patient.

A 2013 report found better monitoring can help prevent the phenomenon.

As for the age-old question about why people need to fast during anesthesia, Lozada said that they should do what their doctors advise.

Fasting guidelines vary depending on the type of procedure and patient, but generally patients cannot eat solid foods for six to eight hours. Many places have become more relaxed about allowing a small-to-moderate amount of clear liquids up to two hours before the procedure, Lozada said.

“You can absolutely risk your health by not fasting,” he explained.

When under anesthesia, the muscles of the stomach and throat relax and that makes it easier to vomit. Because the patient is asleep and cannot protect their airway, vomit can go into the lungs and cause damage during a process known as aspiration pneumonitis.

Understanding propofol

The research sheds light on the mechanisms behind how anesthetics work, though physician anesthesiologists generally understand that, Lozada said.

“The work shows propofol stops some normal cell function, which the authors suggest could lead to general anesthesia,” Lozada said. “More work is needed to definitively show this.”

Choosing which medications are used during a surgery is made by doctors on an individual basis. Factors that go into the selection include heart and lung function, vital signs, overall health, history of anesthesia response, and allergies.

That said, once a patient uses propofol once, it doesn’t necessarily mean they medically can receive it again, he said.

“This is what physician anesthesiologists are trained to assess, and in their hands, it is generally tolerated well,” he said.

Van Swinderen doesn’t want his study to alarm patients.

“People should not be worried about general anesthesia — it works very well. It is just important to know how the drugs we use work, and it is surprising that we still are confused about how this extremely common procedure makes us unconscious and unresponsive,” he said. “Knowing more will help us better solve any side effects.”

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