Some science behind the scenes

Volatile Anaesthetics

The main anaesthetics which come within this classification are:

  • Isoflurane - is a halogenated ether used for inhalational anesthesia. Together with enflurane and halothane, it replaced the flammable ethers used in the pioneer days of surgery. Its use in human medicine has significantly declined, being replaced with sevoflurane, desflurane and the intravenous anaesthetic propofol. Isoflurane is still frequently used for veterinary anaesthesia.  It is always administered in conjunction with air or oxygen
  • Desflurane  - is a highly fluorinated methyl ethyl ether. Together with sevoflurane, it is gradually replacing isoflurane for human use. It has the most rapid onset and offset of the volatile anaesthetic drugs used for general anesthesia due to its low solubility in blood.  Though it vaporises very readily, it is a liquid at room temperature. Anaesthetic machines are fitted with a specialized anaesthetic vaporiser unit that heats liquid desflurane to a constant temperature.  The drawbacks of desflurane are its  pungency and its high cost. Additionally, desflurane is a greenhouse gas.  Desflurane causes 26.8 times the global warming of sevoflurane
  • Halothane [which has been covered separately]
  • Enflurane  -  is a halogenated ether that was commonly used for inhalational anesthesia during the 1970s and 1980s. It vaporizes readily, but is a liquid at room temperature. It is being phased out or has ceased to be used because of its side effects.  Between 2% and 5% of the inhaled dose is oxidised in the liver, producing fluoride ions and difluoromethoxy-difluoroacetic acid which cause liver damage or failure.  Enflurane also lowers the threshold for seizures. It is also known to cause malignant hyperthermia.  Both Enflurane and methoxyflurane have a nephrotoxic effect and cause acute renal failure, usually by its nephrotoxic metabolite.
  • Sevoflurane  - is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether. Together with desflurane, it is replacing isoflurane and halothane in modern anesthesiology.  It is often administered in a mixture of nitrous oxide and oxygen. After desflurane, it is the most volatile anaesthetic with the fastest onset and offset. Though desflurane has the lowest blood/gas coefficient of the currently used volatile anesthetics, it is the preferred agent for mask induction due to its lesser irritation to mucous membranes.  Sevoflurane is a greenhouse gas.  However, the global warming potential of sevoflurane is lower than that of either isoflurane or desflurane.
  • Methoxyflurane – the nephrotoxocity of methoxy flurane is now well established, as such this drug will not be discussed

Of these Isoflurane,  Desflurane and Sevoflurane appear to be more frequently used by the medical profession, clinically and as a ‘spiritual experience’ mechanism.

It may seem highly unlikely to anyone, that anyone would want to ‘abuse’ – that is misuse - anaesthetics for the purpose of getting a spiritual experience.  But it has not passed the medical fraternity by that these particular anaesthetics have the theoretical potential to give you a spiritual experience at low doses.  Of course all poisons do, but they do not think of it as a poison, they think of it as a medicine.  There are a large number of reports in the scientific literature of medical staff – doctors and nurses as well as administrative staff with access to the chemicals by virtue of their job, who have tried these substances.

Some have died in the process. 

J Forensic Sci  1989 Nov;34(6):1408-12. Fatal accidental enflurane intoxication.
Jacob B, Heller C, Daldrup T, Bürrig KF, Barz J, Bonte W.; Department of Forensic Medicine, Heinrich-Heine-University, Düsseldorf, West Germany.
Among reported cases of abuse of volatile anesthetics there is only one of enflurane intoxication. We report another fatal enflurane intoxication. A 21-year-old man found dead seemed to have experimented with enflurane. Three and one-half days after death high amounts of enflurane were detected in blood, brain, and subcutaneous fat. Gas chromatographic quantification revealed the following high enflurane concentrations: blood: 130 mg/l-1, brain: 350 mg/l-1, and subcutaneous fat: 100 mg/l-1. Histologic signs of drug-induced damage were lacking. No suicide intentions became known. It was concluded that the young man died of an accidental intoxication while abusing enflurane.

PMID:  2584946

Although these anaesthetics come in very easy to use small bottles, very different from the enormous bottles of gas one used to see, it is not an easy job to inhale the right amount when you are doing this in a hospital setting on your own and illicitly.  Even anaesthetists get it wrong, which should tell us something about how potentially dangerous they are.

Sevoflurane concentrations in blood, brain, and lung after sevoflurane-induced death.
Rosales CM Young T, Laster MJ, Eger EI 2nd, Garg U.  ;Department of Pathology and Laboratory Medicine, Children's Mercy Hospitals and Clinics, and University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
Sevoflurane concentrations in blood, brain, and lung were measured in an individual apparently dying from sevoflurane inhalation.

Sevoflurane is a volatile nonflammable fluorinated methyl isopropyl ether inhaled anesthetic, chemically related to desflurane and isoflurane. The incidence of abuse of sevoflurane is lower than that of other drugs of abuse possibly due to its inaccessibility to the general public and less pleasurable and addicting effects.

The dead subject was an anaesthetist found prone in bed holding an empty bottle of sevoflurane (Ultane). Serum, urine, and liver were screened for numerous drugs and metabolites using enzyme immunoassays and gas chromatography-mass spectrometry. Analysis did not reveal presence of any drug, including ethanol, other than sevoflurane. Sevoflurane was determined by headspace gas chromatography and revealed concentrations of 15 microg/mL in blood and 130 mg/kg in brain and lung. Autopsy revealed pulmonary edema and frothing in the lung, pathological findings associated with death by sevoflurane or hypoxia. The cause of death was ruled as sevoflurane toxicity and the manner of death as accident.

What is strange is that there is a not a great deal of evidence that these products actually work to give you an experience.  There is a lot of evidence that they send people fairly quickly into a coma, [or kill them] but very little evidence, if any that they give you anything else.  All evidence appears to be circumstantial and may have been obtained from patients as they came out of anaesthesia, or were sedated using these drugs, as opposed to doctors and nurses going into anaesthesia!

Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam--a pilot study - Sackey PV, Martling CR, Carlswärd C, Sundin O, Radell PJ.; Section of Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm, Sweden.
OBJECTIVE:
To compare memories from the intensive care unit (ICU) and short- and long-term psychological morbidity in patients after sedation with intravenous midazolam or inhaled isoflurane.

DESIGN:
Prospective long-term follow-up after randomized controlled trial.

SETTING:
General ICU at Karolinska University Hospital, Solna, Stockholm.

PATIENTS:
Forty patients in need of sedation during ventilator treatment.

INTERVENTIONS:
Patients were randomized to receive isoflurane or midazolam for goal-directed sedation until extubation or for a maximum of 96 hrs.

MEASUREMENTS AND MAIN RESULTS:
For short-term follow-up, doctors', nurses', and physiotherapists' notes from the 4 days following exposure to the study drugs were reviewed for words indicating adequate or pathologic cognitive and psychological recovery. For long-term follow-up, all 6-month survivors received questionnaires including the

  • ICU Memory Tool (ICU-MT)
  • Hospital Anxiety and Depression Scale (HADS)
  • Impact of Event Scale (IES)
  • and Well-Being Index.

Additionally, several screening questions for previous post-traumatic stress symptoms were included.   In the short term follow-up, no significant differences were found between groups.

In the long-term follow-up, a trend toward fewer hallucinations/delusions after isoflurane sedation than after midazolam (two of ten isoflurane patients vs. five of seven midazolam patients) was found (p = .06). None of the five solely isoflurane-sedated patients reported hallucinations/delusions from the ICU. There was no difference in groups in long-term psychological morbidity as measured with HADS and IES. Memories of negative feelings in the ICU (ICU-MT) were associated with high HADS and IES scores (Fisher's exact test, p = .02 and p = .01, respectively).

CONCLUSIONS:
Sedation of ICU patients with isoflurane may result in fewer delusional memories or hallucinations from the ICU compared with more commonly used intravenous sedation. Memories of negative feelings from the ICU were associated with symptoms of depression or anxiety or symptoms indicating post-traumatic stress disorder. Further study of memory and cognitive/psychological recovery after prolonged isoflurane sedation beyond 96 hrs is warranted.

Summary chart based on Meyer’s side effects of drugs

I have relied on Myer’s Side Effects of Drugs to produce this chart.  It is possible that current  research attributes more side effects to Desflurane.  The information on Enflurane is not complete, as the phasing out of Enflurane made it of less interest.

 

Isoflurane

Desflurane

Enflurane

Sevoflurane

Arrhythmia

Note 1

X

 

X

Coronary steal

X Note 6

 

 

 

Respiratory depression

X Note 3

some

 

X

Coughing

X

X

 

 

Vomiting and nausea

X

X

X

X

Bronchodilation

X

 

 

 

Seizures

X

 

X

 

Kidney damage

X

 

X

 

Liver damage

X

X [risk lower]

X

X

Malignant hyperthermia

X

X

X

X

Increased heartrate

 

X

 

 

Vasodilation

 

Possibly

 

 

Respiratory irritant

 

 

 

 

Malignant hypertension

 

 

 

X

Cardiodepressant effects

   

X

X

Pain and shivering

X

 

X

 

Hypotension

X Note 2

 

 

 

Abdominal pain loss of appetite

X

X

 

 

Headache

X

X

 

X

Long term brain damage

 

 

 

X Note 5

 NOTE 1 - Arrhythmias or abnormal heart rate sometimes occurs, resulting in chest pain, shortness of breath or lightheadedness.   Possible complications of arrhythmia include heart failure, the formation of blood clots and an increased likelihood of stroke.

NOTE 2 Low blood pressure or hypotension is another possible cardiovascular side effect of isoflurane, which doctors monitor during the medical procedure.

NOTE 3 A serious respiratory side effect of isoflurane is respiratory depression, a condition that occurs when the  brain fails to properly regulate your breathing, sometimes resulting in heart damage or even death.

NOTE 4 There are some medications which produce unwanted side effects when used in conjunction with isoflurane. For instance, “doctors often avoid other drugs that make you sleepy as this increases your risk of developing respiratory depression. Examples of such drugs include narcotics, sleeping pills and sedatives, anti-epileptic drugs and anti-anxiety medications. In addition, isoflurane increases the effects of muscle relaxants, which both increases your risk of developing side effects from the relaxant and makes it difficult for you to move”.

NOTE 5 - Sevoflurane has been implicated in neuronal degeneration in infant mice. This activity is thought to occur via blockade of NMDA receptors or hyperactivity of GABA neurotransmission. In one study, the researchers showed exposure of infant mice to inhaled sevoflurane resulted in learning deficits and abnormal social behaviour

NOTE 6 - Coronary steal describes an alteration of circulation patterns lead to a reduction in the blood directed to the heart -  "stealing" blood away from the heart.

Some detail behind the findings

For those of you who are interested from a medical perspective here are some papers that support the findings in Myer’s and provide some case histories.

Anaesthesia  1987 Nov;42(11):1191-6. - Hepatotoxicity and death following two enflurane anaesthetics. - Paull JD, Fortune DW; Royal Women's Hospital, Melbourne, Australia.
A 67-year-old woman died with massive fatty change in the liver 41 hours after her second enflurane anaesthetic in 28 days. The clinical features of five previously reported similar deaths are summarised. Possible mechanisms of the hepatotoxicity are reviewed briefly.

Isoflurane hepatotoxicity: a case report and review of the literature.
Sinha A, Clatch RJ, Stuck G, Blumenthal SA, Patel SA.; Department of Family Practice, Christ Hospital and Medical Center, Oak Lawn, Illinois, USA.
Isoflurane, hailed as the anesthetic of the 1980s, is less hepatotoxic than its predecessors, halothane and enflurane. Since its release by the Food and Drug Administration in 1979, controversy has existed about the extent to which isoflurane is capable of producing hepatotoxic effects. In this report, we provide direct evidence that isoflurane can induce liver injury and should therefore be considered as a potential cause of serum transaminase elevations in any patient who is exposed to this anesthetic.

PMID: 8931426

Fatal hepatotoxicity after re-exposure to isoflurane: a case report and review of the literature; Turner GB, O'Rourke D, Scott GO, Beringer TR.
Department of Health Care for the Elderly, Royal Victoria Hospital, Belfast, UK.
A 76-year-old Caucasian woman developed fulminant hepatic necrosis 6 days after an uneventful operation under isoflurane anaesthesia. Laboratory findings included elevated bilirubin, grossly elevated transaminases and prolonged prothrombin time. Radiological investigation showed no evidence of extra-hepatic disease. Serological studies were negative for acute viral hepatitis and autoimmune disease. The patient may have been previously sensitized by exposure to isoflurane 3 years previously but antibodies to tri-fluoro acetate, present in 70% of cases of halothane hepatitis, were not detected in pre-operative or postoperative samples of blood. On the seventh postoperative day the patient died and postmortem examination demonstrated centrilobular necrosis of the liver, with a histological pattern similar to changes associated with halothane hepatitis.

Potential metabolic basis for enflurane hepatitis and the apparent cross-sensitization between enflurane and halothane. - Christ DD, Satoh H, Kenna JG, Pohl LR; Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, Bethesda, MD 20892.
Clinical case reports of unexplained hepatic dysfunction following enflurane and isoflurane anesthesia led to the hypothesis that oxidative metabolism of these drugs by cytochromes P-450 produces immunoreactive, covalently bound acylated protein adducts similar to those implicated in the genesis of halothane-induced hepatic necrosis.

Microsomal adducts were detected by enzyme-linked immunosorbent assay and immunoblotting techniques utilizing specific anti-trifluoroacetyl (TFA) IgG hapten antibodies in rat liver following enflurane, isoflurane, or halothane administration. Preincubation of the antibodies with microsomes from halothane-pretreated rats or with 500 microM TFA-lysine, markedly inhibited adduct recognition, while preincubation with 500 microM acetyllysine had no effect.

The relative amounts of immunoreactive protein adducts formed were halothane much greater than enflurane much greater than isoflurane and correlates directly with the relative extents of metabolism of these agents.

These results support the view that acyl metabolites of the volatile anesthetics may become covalently bound to hepatic proteins, thus serving as antigens, and thereby account for the apparent cross-sensitization and idiosyncratic hepatotoxicity reported for these drugs.

Fulminant hepatic failure after repeated exposure to isoflurane.
Kusuma HR, Venkataramana NK, Rao SA, Naik AL, Gangadhara D, Venkatesh KH.
Department of Anaesthesiology & Critical Care, BGS Global Hospitals, Bangalore, Karnataka, India.
Inhalational agents are used routinely for maintenance of anaesthesia. Post anaesthesia hepatic failure has been documented following exposure to halothane. However, there are very few reports of such complications following isoflurane anaesthesia. A 6-year-old child developed fulminant hepatic failure 2 days following craniotomy under general anaesthesia. There was no evidence of viral, autoimmune, or metabolic causes of hepatitis. No other medications known to cause hepatitis, except low dose paracetamol, were administered. The clinical and histological picture of our case is similar to that of halothane hepatitis, which has a significant mortality rate. We report this as a possible fulminant hepatic failure resulting from exposure to isoflurane anaesthesia

Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury - Njoku D, Laster MJ, Gong DH, Eger EI 2nd, Reed GF, Martin JL.  ;Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
In susceptible patients, halothane, enflurane, isoflurane, and desflurane can produce severe hepatic injury by an immune response directed against reactive anesthetic metabolites covalently bound to hepatic proteins.

The incidence of hepatotoxicity appears to directly correlate with anesthetic metabolism catalyzed by cytochrome P450 2E1 to trifluoroacetylated hepatic proteins. In the present study, we examined whether the extent of acylation of hepatic proteins in rats by halothane, enflurane, isoflurane, and desflurane correlated with reported relative rates of metabolism.

After pretreatment with the P450 2E1 inducer isoniazid, five groups of 10 rats breathed 1.25 minimum alveolar anesthetic concentration (MAC) of halothane, enflurane, isoflurane, or desflurane in oxygen, or oxygen alone, each for 8 h. Immunochemical analysis of livers harvested 18 h after anesthetic exposure showed tissue acylation (greatest to least) after exposure to halothane, enflurane, or isoflurane. Reactivity was not different between isoflurane as compared to desflurane or oxygen alone.

An enzyme-linked immunosorbent assay showed halothane reactivity was significantly greater than that of enflurane, isoflurane, desflurane, or oxygen, and that enflurane reactivity was significantly greater than desflurane or oxygen. Sera from patients with a clinical diagnosis of halothane hepatitis showed antibody reactivity against hepatic proteins from rats exposed to halothane or enflurane. No reactivity was detected in rats exposed to isoflurane, desflurane, or oxygen alone. These results indicate that production of acylated proteins may be an important mediator of anesthetic-induced hepatotoxicity.

Other side effects include respiratory depression, hypotension and tachcardia, shivering and muscle relaxation :

CLINICAL EXPERIENCE WITH ISOFLURANE (FORANE*)  - Preliminary Communication
A. L. PAUCA
, M.D. and R. D. DRIPPS, M.D. Author Affiliations; The Department of Anesthesia, University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 19104, U.S.A.
The clinical anaesthetic course of 100 patients anaesthetized with isoflurane is described. Induction techniques with isoflurane oxygen, nitrous oxide-isoflurane-oxygen, or intravenous thiopentone were devoid of serious complications, the worst being mild excitement. Relaxation for tracheal intubation was excellent. Maintenance of anaesthesia was characterized by:

  • respiratory depression,
  • slight hypotension and tachycardia,
  • good muscle relaxation,
  • compatibility with adrenaline and phenylephrine,
  • absence of ventricular arrhythmias, twitching, convulsions or e.g. seizure patterns.
Nitrous oxide and narcotics decreased the required inspired isoflurane concentration for the same level of anaesthesia. Small doses of tubocurarine produced adequate relaxation. Awakening was rapid, accompanied by pain and shivering in a large proportion of patients. No hypotension was seen during recovery. No postanaesthetic complications were observed

There also seems to be evidence that they make you very sick and give you a headache….

Vomiting, retching, headache and restlessness after halothane-, isoflurane- and enflurane-based anaesthesia. An analysis of pooled data following ear, nose, throat and eye surgery. - van den Berg AA, Honjol NM, Mphanza T, Rozario CJ, Joseph D.; Department of Anaesthesia, Riyadh Armed Forces Hospital, Kingdom of Saudi Arabia.
BACKGROUND:
Isoflurane has exceeded halothane and enflurane in usage. A literature search, however, revealed no data comparing the effects on emesis, headache and restlessness of these three agents.

METHODS:
With hospital ethics committee approval and patient consent, a prospective, randomised, double-blind study of 556 patients undergoing ENT and eye surgery was undertaken to evaluate the effects of halothane, isoflurane and enflurane on vomiting, retching, headache and restlessness until 24 h after anaesthesia. Balanced general anaesthesia was administered comprising benzodiazepine premedication, induction with thiopentone-atracurium-morphine (ENT patients) or fentanyl (eye patients), controlled ventilation and maintenance with either halothane 0.4-0.6 vol% (n = 186), isoflurane 0.6-0.8 vol% (n = 184) or enflurane 0.8-1 vol% (n = 186) in nitrous oxide 67% and oxygen.

RESULTS:
The three study groups were comparable, and comprised comparable subgroups having ear, nose, throat, intraocular and non-intraocular surgery. During early recovery from anaesthesia, the respective requirements for halothane, isoflurane and enflurane for analgesia (7%, 9% and 10%), frequency of emesis (6%, 8% and 8%), antiemetic requirements (1%, 1% and 2%), restlessness-pain scores and time spent in the recovery ward (27 SD 10, 31 SD 12 and 26 SD 9 min) were similar. During the ensuing 24-h postoperative period, patients who had isoflurane experienced emesis less often than those who had halothane (36% vs 46%, P < 0.025) but did so with similar frequency to those who had enflurane (46% vs 41%). Antiemetic requirements were least in those given isoflurane (isoflurane 12%, halothane and enflurane 23% each, P < 0.005), but headache and analgesic requirements were similar.

CONCLUSION:
Isoflurane induces less postoperative emesis than halothane, but headache is similarly frequent after anaesthesia with any of these agents.

Desflurane. A review of its pharmacodynamic and pharmacokinetic properties and its efficacy in general anaesthesia. - Patel SS, Goa KL; Adis International Limited, Auckland, New Zealand.
Desflurane is a halogenated ether inhalation general anaesthetic agent with low solubility in blood and body tissues, and approximately one-fifth the potency of isoflurane. The pharmacodynamic properties of desflurane generally resemble those of isoflurane; thus, it produces dose-dependent depression of the central nervous and cardiorespiratory systems, and tetanic fade at the neuromuscular junction.

The alveolar equilibration of desflurane is rapid (90% complete at 30 minutes compared with 73% for isoflurane). Both desflurane and isoflurane are distributed to various tissues to a similar extent. Desflurane is resistant to chemical degradation and undergoes negligible metabolism (approximately equal to 10% of that seen with isoflurane). Desflurane 'wash-out' is approximately equal to 2 to 2.5 times faster than that of isoflurane in the first 2 hours after discontinuation of anaesthesia. The low solubility of desflurane facilitates a rapid induction of anaesthesia and precise control of the depth of anaesthesia (during maintenance). Results from a few clinical studies indicate that emergence from desflurane is significantly earlier (by approximately equal to 2 to 6 minutes) than that from propofol anaesthesia, whereas other studies do not concur. In comparison with isoflurane, emergence from desflurane anaesthesia is significantly earlier (by 5 minutes) after ambulatory and approximately equal to 50% earlier (also significant) after nonambulatory surgical procedures. Limited comparative studies with halothane or sevoflurane also suggest an earlier time of emergence from desflurane anaesthesia.

Comparative studies of desflurane and propofol, and other inhalation agents, indicate that the times to toleration of oral fluids, sitting and discharge from recovery room are similar, regardless of the general anaesthetic agent administered. However, some limited data in elderly patients (aged > 65 years) suggest that this patient group spends a significantly shorter time in the postanaesthesia care unit after desflurane than after isoflurane anaesthesia.

Differences, if any, in the recovery of cognitive and psychomotor functions after desflurane or propofol anaesthesia remain unclear. However, in comparison with isoflurane anaesthesia, recovery of these functions (up to 45 minutes post-operatively) occurs earlier after desflurane. Significantly fewer patients are subjectively impaired (i.e. drowsy, clumsy, fatigued or confused) upon recovery from desflurane than from isoflurane anaesthesia. Likewise, significantly fewer adult patients are delirious when recovering from desflurane than from isoflurane anaesthesia, though in paediatric patients delirium is more likely when recovering from desflurane than from halothane anaesthesia. Haemodynamic stability during coronary artery surgery is as well maintained with desflurane as with isoflurane, and the drug does not worsen the adverse postoperative outcomes.