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General anesthetics and therapeutic gases
I.D. Welters and M. Leuwer
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General anesthetics and therapeutic gases
ANESTHETIC VAPORS (SEDA-27, 119; SEDA-28, 139; SEDA-29, 129; SEDA-30, 137)
HALOGENATED VAPORS
40 patients (2C). Malondialdehyde concen trations and protein carbonyl content were significantly higher and sulfhydryl groups significantly lower in those who received desflurane.
Desflurane
Susceptibility factors Genetic In a case of malignant hyperthermia there was a negative gradient between arterial and endtidal CO2 during anesthesia, which was used as a diagnostic and monitoring tool (3A).
Respiratory The effect of intravenous fentanyl given before thiopental induction on airway irritation caused by a stepwise increase in desflurane has been studied in 80 children aged 2–8 years in a doubleblind, randomized, placebo-controlled study (1C). Fentanyl reduced the incidence of airway irritation (cough 2.5% versus 43%; secretions 28% versus 83%; excitation 10% versus 83%; apnea 20% versus 65%). The mean expired desflurane concentration at which the first airway irritation symptom occurred was greater with fentanyl.
Smoking Cigarette smokers have a greater risk of respiratory complications during anesthesia than non-smokers, but it is not known to what extent the pungency of inhaled anesthetics contributes. Desflur ane and sevoflurane, the latter being more pungent, have been compared in 55 patients each (4C). There were no differences in the incidences of cough (five versus nine patients respectively), breath holding, lar yngospasm, or desaturation.
(SED-15, 1072; SEDA-30, 137)
Cytotoxicity Free radicals can trigger oxidative stress, leading to the production of malondialdehyde and protein carbonyl content, and the extent of oxidative status can be increased by volatile agents. The effects of sevoflurane+fentanyl, sevoflurane +nitrous oxide, desflurane+fentanyl, and desflurane+nitrous oxide together with pneumoperitoneum have been reported in Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03110-9 r 2009 Elsevier B.V. All rights reserved.
Management of adverse drug reactions In two studies the value of combining antie metic agents in treating postoperative nau sea and vomiting has been demonstrated. Intravenous dexamethasone and tropise tron reduced the incidence of postoperative nausea and vomiting by about 35% in a double-blind, randomized, placebo-controlled study in 320 patients after anesthesia with benzodiazepine premedication, propofol, rocuronium, desflurane in air/O2, and fen tanyl or sufentanil, followed by a contin uous infusion of remifentanil (5C). The two drugs had additive effects, although even in the combination group the incidence of nausea and vomiting was still unacceptably high.
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218 In another randomized, double-blind study in 105 adults undergoing thyroidect omy the addition of propofol 0.5 mg/kg to tropisetron 5 mg improved its antiemetic effects after anesthesia with desflurane (6C) (17% versus 43% with tropisetron alone and 77% with placebo).
Isoflurane (SED-15, 1921; SEDA-30, 138) A Polish Expert Group for Chemical Hazards has suggested that the maximum admissible concentrations for isoflurane in places where it is used should be 32 mg/m3 (4 ppm), and that this limits should protect surgical staff from the adverse neurological, cardiovascular, respiratory, and irritant effects of isoflurane (7RS). Liver Isoflurane-associated hepatotoxicity has been reported (8A). A 68-year-old man developed fulminant fatal
hepatic necrosis 2 days after open cholecys tectomy under isoflurane anesthesia. He had greatly raised transaminases and bilirubin and a prolonged prothrombin time. Serological studies were negative for viral hepatitis. Postmortem examination showed centrilobu lar necrosis of the liver.
Sevoflurane
(SED-15, 3123; SEDA-28, 139; SEDA-29, 129; SEDA-30, 138)
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cardiovascular, respiratory, and irritant effects of sevoflurane (7RS). Cardiovascular The dysrhythmogenic properties of anesthetics are of major concern and there is as yet no safe anesthetic regimen for patients with a prolonged QT interval or those suspected to be at risk. However, electrophysiology experiments have shown that volatile anes thetics, such as sevoflurane, prolong the QT interval by inhibiting the repolarization phase of the action potential. The human ether-a-go-go related gene (HERG) chan nel appears to be involved in this process. A comparison of the effects of sevoflurane and propofol on the QT interval in guinea pigs has confirmed that sevoflurane pro longs the QT interval, and that propofol does not. Furthermore, sevoflurane inhib ited the outward tail currents in HERG channels expressed in Xenopus oocytes, whereas propofol had no effect (10E). In a blinded study in 20 women aged 38–51 years of ASA stages I and II, who were given sevoflurane for total abdominal hysterectomy, there were no significant changes between baseline and final QTc dispersion and between the low- and highfrequency components of heart rate varia bility, despite a significant increase was seen in the variability in RR interval, which was used as a measure of cardiac autonomic tone (11c). An 8-year-old boy with congenital long QT
Occupational exposure to anesthetic gases, such as sevoflurane, can be mitigated by the use of anesthetic gas extractors (9c). In the breathing areas around anesthesiologists mean exposure to sevoflurane without an extractor was 12 ppm. In those who worked with an extractor, exposure was 91% lower (1.1 ppm). There were also higher rates of general discomfort (62% versus 11%), nau sea (62% versus 0%), and headache (62% versus 0%) in the absence of an extractor. A Polish Expert Group for Chemical Hazards has suggested that the maximum admissible concentrations for sevoflurane in places where it is used should be 55 mg/m3 (7 ppm), and that this limits should protect surgical staff from the adverse neurological,
syndrome (LQT2) continued to have attacks of syncope despite nadolol 80 mg/day (12A). He was anesthetized with 2.8–3% sevoflurane for implantation of an internal cardioverter– defibrillator. After 20 minutes he had a run of multifocal ventricular extra beats followed by a spontaneously resolving episode of torsade de pointes lasting 5 seconds. A second episode caused hemodynamic compromise. The sevo flurane was withdrawn and propofol 5 mg/kg/ hour was given intravenously. The dysrhyth mias immediately resolved.
Despite the suggestive time course in this case the association of sevoflurane with torsade de pointes has been challenged (13r). Care is perhaps nevertheless indi cated when using sevoflurane in patients with congenital long QT syndrome (14r).
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Nervous system A 2-year-old child, ASA grade 1, developed myoclonic jerks during anesthesia with sevoflurane (15A). A 23-year-old Taiwanese man with no history
of epilepsy had a generalized convulsion with a mild fever after 11 hours of anesthesia with sevoflurane anesthesia (16A). The episode resolved after aggressive management. Another 3 hours were required to complete the operation and the patient recovered uneventfully.
Sensory systems The effects of anesthetic agents on stapedius reflex thresholds and transient evoked otoacoustic emissions have been studied in 50 patients who were scheduled for operation and who had normal hearing (17c). Anesthesia was main tained with 70% nitrous oxide +30% oxygen, sevoflurane, desflurane, halothane, or intravenous propofol+sufentanil. Mida zolam significantly increased ipsilateral and contralateral stapedius reflex thresholds and reduced the wave reproducibility of the otoacoustic emissions. Propofol signifi cantly increased the stapedius reflex thresholds. The other anesthetic agents significantly increased only the contralat eral reflex thresholds, the largest effect being with sevoflurane and the smallest with halothane. The authors concluded that sevoflurane should not be used when it is necessary to measure stapedius reflex thresholds under general anesthesia. Psychological The effects of brief sevo flurane–nitrous oxide anesthesia on post operative cognition and behavior have been studied in 48 children aged 5–10 years undergoing anesthesia without premedica tion for multiple dental extractions and 48 control children (18c). Mean choice reaction time and psychomotor co-ordination were significantly impaired postoperatively but had recovered by 48 hours, although mea sures of variability suggested residual impairment. There was profound retrograde amnesia postoperatively and at 48 hours, but recognition memory was not impaired. Attention-seeking, tantrums, crying, and nightmares were more frequent in 8–20% of the children 1 week after the procedure.
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Musculoskeletal A patient had two epi sodes of severe muscle rigidity, increased end-tidal CO2, and increased creatine phos phate kinase activity after sevoflurane anesthesia (19A). Genetic testing for the 17 known mutations associated with malignant hyperthermia was negative. Although the authors could not rule out malignant hyperthermia or other neuromuscular dis eases they suggested that this rare event may have been directly due to sevoflurane.
Trichloroethylene (SED-15, 3488; SEDA-28, 140; SEDA-29, 130; SEDA-30, 140) The health risks of trichloroethylene have been reviewed (20R). Respiratory Acute lung damage has been reported in a man who inhaled trichloro ethylene (21A). A 28-year-old man who cleaned tubes that had
been washed with trichloroethylene became unconscious with acute lung injury. ACT scan showed a ground-glass opacity in the left upper lobe. Bronchoalveolar lavage fluid contained alveolar macrophages, lymphocytes, and neutrophils. There were erythrocytes in the alveolar spaces in a lung biopsy and vacuolation of the cytoplasm of type 2 alveolar pneumocytes.
Nervous system Neurotoxicity from tri chloroethylene has again been reported (22A). A 32-year-old male drug addict had temporal
lobe seizures after “huffing” (i.e., voluntarily inhaling) trichloroethylene. He also developed cognitive dysfunction (with memory disorders in particular) and personality changes. These disorders had not been noticed by the patient’s wife before the last episode of inhalation. Four months later, the cognitive disorders had stabilized and he had had no further seizures.
The authors suggested that trichloro ethylene had had a selective effect on the temporal lobe. Skin Workers exposed to trichloro ethylene rarely have severe generalized skin disorders and accompanying hepatitis, which resemble drug hypersensitivity reactions. The
220 effects are distinct from solvent-induced irritating contact dermatitis. In a systematic review of the published literature (239 cases) 124 (52%) cases were classified as hyper sensitivity syndrome and 115 (48%) as erythema multiforme/Stevens–Johnson syn drome/toxic epidermal necrolysis (23M). The reports from Western industrialized coun tries were mostly published up to 1990, whereas cases from Asian industrializing countries appeared thereafter. The association between genetic poly morphisms of human leukocyte antigenDQ (HLA-DQ) and susceptibility to tri chloroethylene-induced severe generalized dermatitis has been investigated in a case– control study in 112 patients with severe generalized dermatitis and 142 healthy con trols exposed to trichloroethylene in the same workshop (24C). The frequencies of DQA1�0201 and 060101/0602 were 7.6% (17/224) and 16% (36/224) in cases, signifi cantly higher than in the exposed controls: 3.5% (10/284) and 7.0% (20/284). The frequencies of DQA1�0103 and 050101/ 0503/0505 were 5.8% (13/224) and 8.9% (20/224) in cases, significantly lower than in exposed controls: 11% (31/284) and 17% (49/284). Five codons of DQA1 (25, 41, 52, 54, and 69) showed significant differences between cases and controls. There were no significant differences in the frequencies of allelic genotypes of HLA-DQB1. In a similar study, the frequencies of HLA-DMA and HLA-DMB have been studied in 61 patients with trichloroethy lene-induced dermatitis and in 60 healthy controls (25C). The frequency of the HLA DMA�0101 allele was significantly higher in the patients than in the controls (71% versus 55%), as was the allele frequency of HLA DMA�0103 (12% versus 3.3%) and the ratio of �0102 homozygotes of HLA DMA�0102 (25% versus 8.2%). The ratio of �0102 heterozygotes of HLA-DMB�0101 was lower in the patients than in the controls. Tumorigenicity Different committees have reported that trichloroethylene is either “probably” (26S) or “reasonably anticipated to be” (27S) carcinogenic in humans. According to the National Toxicology Program “trichloroethylene is reasonably
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I.D. Welters and M. Leuwer
anticipated to be a human carcinogen based on limited evidence of carcinogenicity from studies in humans, sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors at multiple tissue sites in multiple species of experimen tal animals, and information suggesting [that it] acts through mechanisms that indicate it would [probably] cause cancer in humans.” The relative risks, standardized incidence ratios, and standardized mortality ratios from cohort studies and the odds ratios from case–control studies for four types of cancers—liver, liver and biliary tract, and kidney tumors, and non-Hodgkin’s lym phoma—have been reviewed (28RM). The main problems that beset a proper inter pretation of the data are (a) the relative sensitivity of cancer incidence and mortality data; (b) different classifications of lympho mas, including non-Hodgkin lymphoma; (c) differences in data and methods for assign ing trichloroethylene exposure status; and (d) different methods used for making causal inferences, including statistical approaches and meta-analyses. However, the overall data suggest that there are increased risks of cancers of the kidney, liver, and lymphatic systems in those who are occupationally exposed to trichloroethy lene, with typical relative risks of 1.5–2.0. In a meta-analysis of 14 occupational cohort and four case–control studies of workers exposed to trichloroethylene the summary relative risk estimates for non Hodgkin’s lymphoma from the cohort studies was 1.29 (95% CI ¼ 1.00, 1.66) for the total cohort and 1.59 (95% CI ¼ 1.21, 2.08) for the seven studies that identified a specific sub-cohort that had been exposed to trichloroethylene (29M). However, com parison of the relative risk estimates by trichloroethylene exposure did not indicate a dose–response effect. Case–control stu dies had a summary relative risk estimate of 1.39 (95% CI ¼ 0.62, 3.10). The interpreta tion of the results of this analysis was hampered by variability in results across the studies, limited assessments of expo sure, lack of supportive information from toxicological and mechanistic data, and the
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absence of consistent findings. Although there was a modest positive association in the sub-cohort analysis, there was insuffi cient evidence to suggest a causal link between exposure to trichloroethylene and non-Hodgkin’s lymphoma. The carcinogenic effects of trichloroethy lene may be at least partly medicated by its metabolites dichloroacetic acid and trichlor oacetic acid (30E). A meta-analysis of epidemiological stu dies of occupational exposure to trichlor oethylene has shown no association with either multiple myeloma or leukemia (31M). Teratogenicity The risks of congenital heart defects after exposure to trichloroethy lene have been analyzed by a systematic review of the epidemiological data and animal studies (32M). No single process was clearly affected by trichloroethylene, provid ing support that gestational exposure does not increase the prevalence of congenital heart defects. Application of Bradford Hill’s causality guidelines showed no causal link.
OTHER VAPORS
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by arm weakness, leg paraplegia, and neuro genic bladder (33A). He had hyperhomo cysteinemia and a low serum vitamin B12 concentration. There was a polymorphism in the MTHFR gene associated with the thermolabile isoform of the 5,10-methylene tetrahydrofolate reductase enzyme, which explained the myelopathy after exposure to nitrous oxide. Therapy with folic acid and vitamin B12 resolved the neurological symptoms. Drug abuse In a 33-year-old man nitrous oxide abuse caused vitamin B12 deficiency, which resulted in bizarre behavior and delusions, which responded to treatment with intramuscular cobalamin (34A). Management of adverse drug reactions Occupational exposure to anesthetic gases, such as nitrous oxide, can be mitigated by the use of anesthetic gas extractors (9c). In the breathing areas around anesthesiologists mean exposure to nitrous oxide without an extractor was 423 ppm. In those who worked with an extractor, exposure was 94% lower (25 ppm). There were also higher rates of general discomfort (62% versus 11%), nausea (62% versus 0%), and headache (62% versus 0%) in the absence of an extractor.
Nitrous oxide
(SED-15, 2550; SEDA28, 140; SEDA-29, 131; SEDA-30, 140)
Observational studies The adverse effects of a 50% nitrous oxide/oxygen mixture have been studied in a 4-year prospective survey of 35942 data sheets received from 191 French hospital pediatric units (82%) and adult units (18%), of which 35828 were sufficiently complete to be used. There were 1581 (4.4%) adverse events reported on 1384 data sheets, mostly gastrointestinal and neuropsychiatric disorders (86%). The main factors associated with adverse events were age, concomitant drugs, and longer duration of inhalation. Of 27 (0.08%) serious adverse events, only 9 (0.03%) were possibly attributable to the mixture. Nervous system A patient who received nitrous oxide on two occasions in 8 weeks developed a diffuse myelopathy, characterized
INTRAVENOUS AGENTS: NON-BARBITURATE ANESTHETICS Etomidate (SED-15, 1302; SEDA-30, 140) Nervous system Myoclonic movements and pain on injection are common during induction of anesthesia with etomidate. The bispectral index is commonly used to judge the level of anesthesia and provides a single dimensionless number derived from a Fourier transform of the electroencephalogram. A value of 0 indicates electroencephalographic silence, 100 is the expected value in a fully awake individual, and values between 40 and 60 are considered appropriate during general anesthesia. Electromyographic activity of the
222 facial muscles is one of the signals used by the bispectral index algorithm. Changes in the bispectral index have been documented in a patient with involuntary movements of the facial muscles during a severe episode of etomidate-induced myoclonus (35A). A 51-year-old man with no personal or family
history of epilepsy underwent general anesthe sia for excision of an anal polyp. Premedica tion consisted of oral midazolam. Anesthesia was induced with intravenous fentanyl fol lowed by an infusion of etomidate 5 mg/minute to a total of 20 mg. Shortly after losing his response to verbal commands, he started to have twitching of the muscles around the mouth, followed by tonic-clonic movements of the arms and legs. The bispectral index, which had fallen to a minimum of 40, increased rapidly to above 70. The involuntary movements ceased after an intravenous bolus of propofol 70 mg. Anesthesia was then main tained with nitrous oxide and sevoflurane. Recovery was uneventful and he had no recall of any of the events.
Myoclonus induced by etomidate appears to be different from epilepsy, as it is not associated with seizure-like electro encephalographic activity (36c). In this case, when the movements were terminated with a bolus injection of propofol, the bispectral index rapidly fell to a value consistent with anesthesia. In contrast to previous studies in which changes in bispectral index were investigated after induction with etomidate, this patient was not paralysed and devel oped myoclonic movements soon after losing consciousness. The analgesic properties and in particular the inhibitory effects of etomidate on spinal cord neuronal responses to noxious stimuli have been investigated in rats, which were anesthetized with isoflurane (37E). Lami nectomy was performed to record single unit activity. Lumbar neuronal responses to noxious thermal stimulation of the hindpaw were recorded before and every 2 minutes after administration of etomidate. The responses at peak effect of etomidate were reduced to 36% of the control response, depending on the dose (0.125, 0.25, 0.5, 1, and 2 mg/kg). The responses usually recovered within 10 minutes after injection. There were similar effects in decerebrate isoflurane-free rats. The authors concluded
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that etomidate depresses spinal cord neu ronal responses to noxious stimulation and that this might be a possible mechanism by which etomidate produces analgesia.
Ketamine (SED-15, 1964; SEDA-28, 141; SEDA-29, 131; SEDA-30, 141) Nervous system Ketamine potentiates intravenous or epidural morphine analgesia. The effect of an infusion of a very low dose of ketamine on acute and long-term postthoracotomy pain has been studied in 49 patients who were randomly assigned to one of two regimens: continuous epidural infusion of ropivacaine+morphine for 2 days, along with an intravenous infusion of ketamine 0.05 mg/kg/hour or placebo for 3 days (38c). Postoperative visual analog scale scores and numerical rating scale scores 1 and 3 months after surgery were lower after ketamine. Three months after surgery, more control patients were taking pain medications.
Propofol
(SED-15, 2945; SEDA-28, 142; SEDA-29, 132; SEDA-30, 142) Cardiovascular Because of its fast onset and offset of hypnotic action and its short, context-sensitive half-life, propofol is an attractive intravenous anesthetic for induction and maintenance of anesthesia. Several aspects of its interactions with the cardiovascular system in patients with left ventricular dysfunction have been reviewed (39R). Propofol reduces arterial blood pressure, mainly by reducing sympathetic tone, vascular resistance, and preload, and not by impairing myocardial contractility. Although it has negative inotropic effects, partly mediated by reduced uptake of calcium into the sarcoplasmic reticulum, they do not appear to be clinically important. It is not clear, however, how propofol affects cardiovascular function in patients with severe left ventricular dysfunction. Experiments in rodents have not shown any effects in compensated or congenital hypertrophic cardiomyopathy, and a study on left ventricular trabeculae from pigs with pacing-induced congestive heart failure suggested that the myocardial
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depressive effects of propofol might be more pronounced in the presence of left ventricular dysfunction than in healthy hearts (40E). In dogs with dilated cardiomyopathy induced by continuous pacing at 240 Hz for up to 3 weeks, propofol reduced left ventricular preload, afterload, and regional chamber stiffness, caused a dose-related direct negative inotropic effect, and impaired early diastolic left ventricular filling (41E). The protective effects of propofol in ischemia/reperfusion injury have been reviewed. Propofol inhibits specific subu nits of KATP channels, but only in con centrations 5–15 times higher than those encountered during clinical anesthesia (42R). Protection may also be provided by scavenging of free oxygen radicals, reduced disulfide bonding in proteins, and inhibition of lipid peroxidation. Additional protective effects may be related to inhibi tion of the mitochondrial permeability transition pore, which represents opening of non-specific pores in the inner mito chondrial membrane under conditions of increased oxidative stress. The authors concluded that propofol causes only mini mal myocardial depression in the healthy heart at clinically relevant concentrations, but that the risk of cardiac depression may be increased in the failing heart. It should therefore be administered slowly, in order to allow the cardiovascular system to compensate for the associated hemody namic changes. For intravenous anesthesia, propofol should be combined with opioids, which have relatively few cardiovascular adverse effects and also protect against ischemia/reperfusion injury. Respiratory General anesthesia can cause airway compromise. In a prospective study in nine infants undergoing elective MRI scanning of the brain, spin echo magnetic resonance images of the airways were acquired during different stages of propofol anesthesia (80 and 240 mg/kg/minute) with and without 10 mmHg continuous positive airway pressure (43c). At each anatomical level, airway caliber fell as the depth of propofol anesthesia increase, an effect that was completely reversed by continuous
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positive airway pressure. This study has highlighted the need for appropriate airway support as the depth of anesthesia increases, even if spontaneous ventilation is maintained. Nervous system There is a debate about whether propofol has proconvulsant or anticonvulsant effects and whether it should be used in patients with epilepsy. The effects of intravenous propofol on the electroencephalogram have been assessed prospectively in children with epilepsy (44c). There were no seizure-like phenom ena during and after propofol sedation. Immediately after withdrawal of propofol, the characteristic electroencephalographic patterns in children with epilepsy consisted of transient increased beta wave activity (23/25 children) and suppression of pre existing theta rhythms (11/16 children). In addition, spike-wave patterns were sup pressed after propofol sedation (16/18 children with epilepsy). In 25 children with learning difficulties there was a transient increase in beta wave activity and there was suppression of theta rhythms in 11 of 12 children. The results of this study have supported the concept that propofol has anticonvulsant properties. In neuroanesthesia propofol has advan tages over volatile anesthetics (45R). The authors regard propofol as first-choice anesthetic, because it is associated with lower intracranial pressure and cerebral swelling than volatile anesthetics in patients with brain tumors undergoing craniotomy, hardly interferes with somatosensory, audi tory and motor evoked potentials, and provides excellent and predictable recovery conditions as well as minimal postoperative adverse effects. Similar to cardiovascular protection, the potential neuroprotective effect of propofol may be mediated by antioxidant effects. Metabolism The propofol infusion syndrome is the commonest cause of death directly related to the use of propofol, and deaths associated with the use of propofol for sedation have been reviewed (46M). All reports of deaths after sedation with pro pofol in children and adults submitted to
224 the Food and Drug Administration (FDA) and entered into its post-marketing drug safety database were considered, as were published reports and studies. The propofol infusion syndrome was defined as metabolic acidosis and/or rhabdomyolysis with pro gressive myocardial failure. Between 1989 and April 2005, the Adverse Event Report ing System of the FDA received reports of 21 patients aged 16 years or under and 68 patients aged over 16 years who died after administration of propofol for non-proce dural sedation. The most frequent symp toms were progressive cardiac dysfunction/ failure (bradycardia, cardiac failure, “cardio vascular collapse”, dysrhythmias, and cardiac arrest), metabolic acidosis, hypoten sion, and rhabdomyolysis. Additional symp toms described in the adults were renal failure, respiratory failure/adult respiratory distress syndrome, persistent sedation, hyperthermia/fever, hypertriglyceridemia, multiorgan failure, liver dysfunction, tre mors/weakness/polyneuropathy/movement disorders in five, sepsis in five, hepatic failure in four, and hyperkalemia. However, the specificity of the latter symptoms for propofol infusion syndrome is questionable. The authors concluded that some adult deaths and a large number of children’s deaths reported in the post-marketing drug safety database of the FDA have a striking similarity in clinical characteristics, course of illness, and propofol dose and duration to published reports and studies of the propofol infusion syndrome. This review and the many published case reports must lead to the recommendation that propofol in higher doses, in higher concentrations, and for longer durations must be avoided in both children and adults. Doses of propofol should be kept as low as effectively possible, and regular hemodynamic and blood gas monitoring is necessary in patients who are sedated with propofol, in order to detect early signs of cardiovascular failure and lactic acidosis. As previously recommended by the American College of Critical Care Medicine (47S), alternative sedative agents should be con sidered for patients who develop increasing requirements for vasopressors or inotropes
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or cardiac failure during high-dose propofol infusion. The propofol infusion syndrome has been reported in a young patient with traumatic brain injury, which is a suscept ibility factor, as high doses are often required to achieve a satisfactory degree of sedation and/or to control raised intra cerebral pressure (48A). A 21-year-old man with traumatic brain injury
was given high doses of propofol for sedation and control of intracranial pressure, combined with vasopressor therapy to maintain a cere bral perfusion pressure above 60 mmHg. He developed a significant metabolic acidosis with a lactic acid concentration of 11 mmol/l. Exploratory abdominal laparotomy showed no traumatic injury. During the procedure, the propofol infusion was discontinued and the lactic acidosis improved. An echocardiogram showed severe left ventricular dysfunction and cardiomyopathy, which resolved within 19 days.
The authors thought that a combination of high-dose propofol and catecholamines had been responsible for the lactic acidosis in this case. In addition, the use of intravenous inotropes may aggravate lactic acidosis or even trigger the propofol infu sion syndrome. In this case, early diagnosis and immediate withdrawal of propofol may have contributed to the complete reversal of symptoms and the favorable outcome. Liver Postoperative serum aspartate transaminase, alanine transaminase, and lactate dehydrogenase activities increased transiently after the use of propofol in 160 patients undergoing elective coronary artery surgery, more so than in 160 patients who were given sevoflurane (49c). Lactation The transfer of propofol into breast milk has been studied in five women (50c). They were premedicated with mid azolam before induction of anesthesia with propofol and fentanyl. Anesthesia was main tained with volatile anesthetics. During 24 hours of milk collection, 0.004–0.082% of the dose of propofol was excreted into the milk. Although evidence is scarce, lactating women are frequently advised to pump and discard their milk for 24 hours after the
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operations requiring general anesthesia. However, based on these results, the authors concluded that interrupting breast-feeding in this way is not justified. Susceptibility factors Age The effects of age on sedation induced by propofol and midazolam have been studied in patients under and over 65 years undergoing cardi oversion in a randomized study (51C). Mean induction times were similar. However, mean recovery time was shorter in those who received propofol and in patients under 65 years. Older participants needed less medication. There were no hemodynamic differences between the groups, but desa turation was higher in the patients who received midazolam. Hemorrhage Four patients with advanced cirrhosis became hemodynamically unstable as a result of massive blood loss during surgery; this was associated with increases in total propofol (twofold) and unbound pro pofol (fourfold) (52c). All were resuscitated within 60 minutes. Propofol is highly bound to plasma albumin, erythrocytes, and lipo proteins, and the unbound fraction is usually under 3%. Changes in protein binding and reduced renal and hepatic blood flow during shock can alter the clearance of propofol. Drug formulations There has been a report of complications associated with propofol, owing to malfunction of a com mon drug infusion pump (53A). The syringe saddle was missing and allowed the syringe barrel to contact the pump case, which reduced outward displacement of the syr inge clamp. The infusion pump then falsely detected a smaller syringe size and conse quently delivered an increased infusion rate, resulting in propofol overdose. More commonly, an incorrectly mounted syringe may increase outward displacement of the syringe clamp, so that the infusion pump falsely detects a larger syringe size; this results in a reduced infusion rate. Generic propofol (with a sulfite additive) and Diprivan have been compared in a randomized, double-blind study in 60
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women undergoing abdominal hysterectomy (54c). The mean drug doses adjusted for weight and time were similar, and similar blood propofol concentrations were needed to adjust the depth of anesthesia to a bispectral index of 50–65. Propofol is lipid-soluble and is formu lated as a water-in-oil emulsion, which has drawbacks, such as injection pain and micro-organism contamination. A lipid-free formulation of propofol became available in India in 2006 (Cleofol 1%, Themis Pharmaceuticals, Mumbai). However, sev eral adverse effects of this formulation, which contained thiomersal as a preserva tive, were reported, including extravasation (55A) and acute venous thrombosis (56A). A 48-year-old woman was given Cleofol 10 ml
premixed with lidocaine via a cannula in the most prominent vein on the dorsum of the left hand. In the postanesthesia care unit, extra vasation was observed. She complained of severe pain in her left hand. The skin was erythematous and swollen. The radial pulse was easily palpable. Her left arm was raised and subcutaneous hyaluronidase was injected. Over the next 4 hours the edema increased and the hand was swollen, tense, and cyanotic, with delayed capillary refill. The skin of the dorsum of the left hand was incised, the tissues were flushed out with 500 ml of isotonic saline, and drains were inserted for 24 hours. A layer of betadine soaked gauge was applied to the wound. Four weeks later, the site of extra vasation had healed without any undue sequelae. A 55-year-old woman with well-controlled hypertension was given Cleofol 1.5 mg/kg through an intravenous cannula in the left forearm. At the time of injection she com plained of severe pain in the forearm and arm, which subsided after flushing the cannula with isotonic saline. Two subsequent injections of propofol also caused severe pain. Following the fourth bolus of propofol the patient awoke with excruciating pain in the limb. The super ficial veins of the left forearm became promi nent, tender, and cord-like and the peripheral blood oxygen saturation monitored in the left index finger fell to 78–80%. The left forearm and hand were swollen, dusky blue, and cold. There was retrograde flow of blood into the intravenous giving set. The intravenous infu sion in the left forearm was discontinued and a new line started in the right hand. Efforts to flush the cannula in the left forearm were unsuccessful, but a 5-cm blood clot was aspi rated. Doppler examination showed blockage of
226 the brachial vein in the left antecubital fossa and compression of the brachial artery by grossly engorged brachial veins.
In the second case the reduction in peripheral blood oxygen saturation in the affected limb was probably related to compression of brachial artery by engorged brachial veins and by edema due to deep vein obstruction. Drug administration route Accidental injection of propofol and remifentanil into the cerebroventricular compartment has been reported (57A). A 51-year-old patient was accidentally given
remifentanil 150 mg and 10 ml of propofol 1% through an intracerebroventricular totally implantable access port placed in the right infraclavicular region, which was mistakenly thought to be an intravenous line. Severe pain in the head and neck caused the mistake to be discovered rapidly, and 20 ml of a mixture of cerebrospinal fluid and the anesthetic drugs were aspirated from the implantable access port. There were no apparent adverse neuro logical sequelae.
Management of adverse drug reactions Pain on injection with propofol occurs in about 70% of patients (SEDA-30, 143), and there have been many studies, with varying success, of ways of minimizing the pain. Low-dose ketamine seems promising in reducing injection pain and in mitigating the respiratory depression and hypotension associated with propofol (58c). Low doses
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I.D. Welters and M. Leuwer
of ketamine have been compared with saline and lidocaine in 240 patients in order to establish the optimal dose for prevention of pain after propofol injection (59C). Ketamine 100 mg/kg immediately before propofol injection was the optimal dose and timing to reduce propofol-induced pain on injection.
INTRAVENOUS AGENTS: BARBITURATE ANESTHETICS Thiopental sodium
(SED-15, 3395;
SEDA-30, 146) Monitoring therapy There has been a survey of how thiopental was used in UK neurosurgery critical care units (60A). It was used in 23 out of 26 participating units, and 14 had a protocol or guidelines of its use. Cerebral monitoring was used to guide dosage in 17 units. Twenty units delayed brain stem testing when patients had had thiopental, two would not perform tests at all, and one incorporated cerebral angiography into their protocol. This survey demonstrates a lack of uniform management regimens for brain stem testing after the administration of thiopental. There is clearly a need to clarify when brain stem testing should be performed in such cases, if at all.
References 1. Lee J, Oh Y, Kim C, Kim S, Park H, Kim H. Fentanyl reduces desflurane-induced airway irritability following thiopental administration in children. Acta Anaesthesiol Scand 2006; 50(9):1161–4. 2. Sivaci R, Kahraman A, Serteser M, Sahin DA, Dilek ON. Cytotoxic effects of volatile anes thetics with free radicals undergoing laparo scopic surgery. Clin Biochem 2006;39(3): 293–8.
3. Kwetny I, Finucane BT. Negative arterial to end-tidal carbon dioxide gradient: an addi tional sign of malignant hyperthermia during desflurane anesthesia. Anesth Analg 2006; 102(3):815–7. 4. McKay RE, Bostrom A, Balea MC, McKay WR. Airway responses during desflurane versus sevoflurane administration via a lar yngeal mask airway in smokers. Anesth Analg 2006;103(5):1147–54.
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5. Eberhart LH, Büning EK, Folz B, May bauer DM, Kästner M, Kalder M, Koch T, Kranke P, Wulf H. Anti-emetic prophylaxis with oral tropisetron and/or dexametha sone. Eur J Clin Invest 2006;36(8):580–7. 6. Akin A, Esmaoglu A, Gunes I, Boyaci A. The effects of the prophylactic tropisetron propofol combination on postoperative nausea and vomiting in patients undergoing thyroidectomy under desflurane anesthesia. Mt Sinai J Med 2006;73(2):560–3. 7. Kupczewska-Dobecka M, So�cko R. Ocena ryzyka zwiazanego z narazeniem personelu medycznego na dzialanie sewofluranu i izofluranu, wziewnych srodkow anestetycz nych–problem dla pracodawcow. [Assessment of health risk of sevoflurane and isoflurane exposure among surgical staff: a problem for employers.] Med Pr 2006;57(6): 557–66. 8. Ihtiyar E, Algin C, Haciolu A, Isiksoy S. Fatal isoflurane hepatotoxicity without re-exposure. Indian J Gastroenterol 2006; 25(1):41–2. 9. Sanabria Carretero P, Rodríguez Pérez E, Jiménez Mateos E, Palomero Rodríguez E, Goldman Tarlousky L, Gilsanz Rodriguez F, García Caballeroa J. Exposicion laboral al oxido nitroso y sevoflurano durante la anestesia en pediatraa: evaluacion de un dispositivo de extraccion de gases anestesi cos. [Occupational exposure to nitrous oxide and sevoflurane during pediatric anesthesia: evaluation of an anesthetic gas extractor.] Rev Esp Anestesiol Reanim 2006;53(10):618–25. 10. Yamada M, Hatakeyama N, Malykhina AP, Yamazaki M, Momose Y. Akbarali HI. The effects of sevoflurane and propofol on QT interval and heterologously expressed human ether-a-go-go related gene currents in Xenopus oocytes. Anesth Analg 2006; 102(1):98–103. 11. Ugur B, Sen S, Tekten T, Odabasi AR, Yüksel H, Ogurlu M, Onbasili A. Effects of sevoflurane on QT dispersion and heart rate variability. Adv Ther 2006;23(3):439–45. 12. Saussine M, Massad I, Raczka F, Davy JM, Frapier JM. Torsade de pointes during sevoflurane anesthesia in a child with congenital long QT syndrome. Paediatr Anaesth 2006;16(1):63–5.
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13. Whyte SD, Sanatani S, Booker PD. Tor sades de pointes with sevoflurane. Paediatr Anaesth 2006;16(11):1199–201. 14. Saussine M. Torsades de pointes with sevoflurane. Author's reply. Paediatr Anaesth 2006;16(11):201. 15. Leclerc C, Vauguet E. Myoclonies induites par le sévoflurane chez l'enfant. [Seizure- like movements in a child undergoing sevoflurane anaesthesia.] Ann Fr Anesth Reanim 2006;25(8):903. 16. Poon KS, Fung ST, Jeng LB, Wu RS. Seizure attack during partial hepatectomy in a living donor for liver transplantation under sevoflurane anesthesia. Acta Anaes thesiol Taiwan 2006;44(2):123–6. 17. Guven S, Tas A, Adali MK, Yagiz R, Alagol A, Uzun C, Koten M, Karasalihoglu AR. Influence of anaesthetic agents on transient evoked otoacoustic emissions and stapedius reflex thresholds. J Laryngol Otol 2006;120(1):10–5. 18. Millar K, Asbury AJ, Bowman AW, Hosey MT, Musiello T, Welbury RR. The effects of brief sevoflurane-nitrous oxide anaesthesia upon children's postoperative cognition and behaviour. Anaesthesia 2006;61(6): 541–7. 19. Cohen IT, Kaplan R. Repeat episodes of severe muscle rigidity in a child receiving sevoflurane. Paediatr Anaesth 2006;16(10): 1077–9. 20. National Center for Environmental Assessment. Trichloroethylene Health Risks: Key Scientific Issues. http://cfpub.epa.gov/ncea/ cfm/recordisplay.cfm?deid¼119268. 21. Morimatsu Y, Ishitake T, Irie K, Hara K, Sakamoto T, Aizawa H. Acute pulmonary injury due to exposure to a high concentra tion of trichloroethylene vapor. J Occup Health 2006;48(4):271–2. 22. Mutez E, Le Rhun E, Perriol MP, Soto Arès G, Pécheux N, Destée A, Defebvre L. Crises temporales symptomatiques d’une intoxication au trichloroethylene. [Trichloro ethylene intoxication presenting with temporal seizures.] Rev Neurol (Paris) 2006; 162(12):1248–51. 23. Kamijima M, Hisanaga N, Wang H, Nakajima T. Occupational trichloroethylene exposure as a cause of idiosyncratic general ized skin disorders and accompanying
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Chapter 10 hepatitis similar to drug hypersensitivities. Int Arch Occup Environ Health 2007;80(5): 357–70. Li HS, Dai YF, Huang HL, Feng XL, Sun YF, Niu Y, Cheng J, Zhang LY, Li LY, Chen B, Zheng YX. [Possible association between polymorphisms of human leuko cyte antigen-DQ genes and susceptibility to trichloroethylene-induced severe general ized dermatitis.] Zhonghua Yu Fang Yi Xue Za Zhi 2006;40(3):173–6. Yue F, Huang HL, Huang ZL, Li LY, Liang LY, Chen XM. [Relationship of trichlor oethylene-induced medicamentosa like der matitis to HLA-DMA and HLA-DMB.] Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2006;24(5):263–5. International Agency for Research on Cancer. Dry cleaning, some chlorinated solvents and other industrial chemicals. IARC Monogra Eval Carcinog Risks Hum 1995;63:74–158. National Toxicology Program. Report on Carcinogens. 11th ed. Research Triangle Park, NC. http://ntp.niehs.nih.gov/ntp/roc/ eleventh/profiles/s180tce.pdf. Scott CS, Chiu WA. Trichloroethylene cancer epidemiology: a consideration of select issues. Environ Health Perspect 2006;114(9):1471–8. Mandel JH, Kelsh MA, Mink PJ, Alexander DD, Kalmes RM, Weingart M, Yost L, Goodman M. Occupational trichloroethy lene exposure and non-Hodgkin's lym phoma: a meta-analysis and review. Occup Environ Med 2006;63(9):597–607. Caldwell JC, Keshava N. Key issues in the modes of action and effects of trichloroethylene metabolites for liver and kidney tumorigenesis. Environ Health Perspect 2006;114(9):1457–63. Alexander DD, Mink PJ, Mandel JH, Kelsh MA. A meta-analysis of occupational tri chloroethylene exposure and multiple myeloma or leukaemia. Occup Med (Lond) 2006;56(7):485–93. Watson RE, Jacobson CF, Williams AL, Howard WB, DeSesso JM. Trichloroethy lene-contaminated drinking water and con genital heart defects: a critical analysis of the literature. Reprod Toxicol 2006;21(2): 117–47.
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33. Lacassie HJ, Nazar C, Yonish B, Sandoval P, Muir HA, Mellado P. Reversible nitrous oxide myelopathy and a polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase. Br J Anaesth 2006; 96(2):222–5. 34. Sethi NK, Mullin P, Torgovnick J, Capasso G. Nitrous oxide “whippit” abuse present ing with cobalamin responsive psychosis. J Med Toxicol 2006;2(2):71–4. 35. Lim TA, Lim KY. BIS during etomidate induced myoclonus. Anaesthesia 2006;61(4): 410–1. 36. Doenicke AW, Roizen MF, Kugler J, Kroll H, Foss J, Ostwald P. Reducing myoclonus after etomidate. Anesthesiology 1999;90(1): 113–9. 37. Mitsuyo T, Antognini JF, Carstens E. Etomidate depresses lumbar dorsal horn neuro nal responses to noxious thermal stimulation in rats. Anesth Analg 2006;102(4):1169–73. 38. Suzuki M, Haraguti S, Sugimoto K, Kiku tani T, Shimada Y, Sakamoto A. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesio logy 2006;105(1):111–9. 39. Bovill JG. Intravenous anesthesia for the patient with left ventricular dysfunction. Semin Cardiothorac Vasc Anesth 2006;10(1): 43–8. 40. Hebbar L, Dorman BH, Clair MJ, Roy RC, Spinale FG. Negative and selective effects of propofol on isolated swine myocyte contractile function in pacing-induced con gestive heart failure. Anesthesiology 1997; 86(3):649–59. 41. Pagel PS, Hettrick DA, Kersten JR, Lowe D, Warltier DC. Cardiovascular effects of propofol in dogs with dilated cardiomyopathy. Anesthesiology 1998;88(1): 180–9. 42. Kawano T, Oshita S, Takahashi A, Tsutsumi Y, Tomiyama Y, Kitahata H, Kuroda Y, Nakaya Y. Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate sensitive potassium channels. Anesthesiology 2004;100(2):338–46. 43. Crawford MW, Rohan D, Macgowan CK, Yoo SJ, Macpherson BA. Effect of propofol anesthesia and continuous positive airway pressure on upper airway size and
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44.
45.
46.
47.
48.
49.
50.
51.
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configuration in infants. Anesthesiology 2006;105(1):45–50. Meyer S, Shamdeen MG, Kegel B, Mencke T, Gottschling S, Gortner L, Grundmann U. l Effect of propofol on seizure-like phenom ena and electroencephalographic activity in children with epilepsy vs children with learning difficulties. Anaesthesia 2006;61(11): 1040–7. Hans P, Bonhomme V. Why we still use intravenous drugs as the basic regimen for neurosurgical anaesthesia. Curr Opin Anaesthesiol 2006;19(5):498–503. Wysowski DK, Pollock ML. Reports of death with use of propofol (Diprivan) for nonprocedural (long-term) sedation and lit erature review. Anesthesiology 2006;105(5): 1047–51. Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM, Crippen DW, Fuchs BD, Kelleher RM, Marik PE, Nasraway Jr. SA, Murray MJ, Peruzzi WT, Lumb PD. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30(1):119–41. Corbett SM, Moore J, Rebuck JA, Rogers FB, Greene CM. Survival of propofol infusion syndrome in a head-injured patient. Crit Care Med 2006;34(9):2479–83. Lorsomradee S, Cromheecke S, Lorsomra dee S, De Hert SG. Effects of sevoflurane on biomechanical markers of hepatic and renal dysfunction after coronary artery surgery. J Cardiothorac Vasc Anesth 2006; 20(5):684–90. Nitsun M, Szokol JW, Saleh HJ, Murphy GS, Vender JS, Luong L, Raikoff K, Avram MJ. Pharmacokinetics of midazolam, propofol, and fentanyl transfer to human breast milk. Clin Pharmacol Ther 2006;79(6):549–57. Parlak M, Parlak I, Erdur B, Ergin A, Sagiroglu E. Age effect on efficacy and side
52.
53.
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60.
229 effects of two sedation and analgesia pro tocols on patients going through cardiover sion: a randomized clinical trial. Acad Emerg Med 2006;13(5):493–9. Takizawa D, Takizawa E, Miyoshi S, Kawahara F, Hiraoka H. The increase in total and unbound propofol concentrations during accidental hemorrhagic shock in patients undergoing liver transplantation. Anesth Analg 2006;103(5):1339–40. Koch C, Hollister C, Breen PH. Infusion pump delivers over-dosage of propofol as a result of missing syringe support. Anesth Analg 2006;102(4):1154–6. Olufolabi AJ, Gan TJ, Lacassie HJ, White WD, Habib AS. A randomized, prospective double-blind comparison of the efficacy of generic propofol (sulphite additive) with diprivan. Eur J Anaesthesiol 2006;23(4): 341–5. Mahajan R, Gupta R, Sharma A. Extra vasation injury caused by propofol. Anesth Analg 2006;102(2):648. Reddy KR, Chandramouli BA, Rao GS. Acute venous thrombosis caused by lipid free propofol. Anaesthesia 2006;61(3):300–1. Tiefenthaler W, Tschupik K, Hohlrieder M, Eisner W, Benzer A. Accidental intracerebroventricular injection of anaesthetic drugs during induction of general anaes thesia. Anaesthesia 2006;61(12):1208–10. Tomatir E, Atalay H, Gurses E, Erbay H, Bozkurt P. Effects of low dose ketamine before induction on propofol anesthesia for pediatric magnetic resonance imaging. Pae diatr Anaesth 2004;14(10):845–50. Koo SW, Cho SJ, Kim YK, Ham KD, Hwang JH. Small-dose ketamine reduces the pain of propofol injection. Anesth Analg 2006;103(6):1444–7. Pratt OW, Bowles B, Protheroe RT. Brain stem death testing after thiopental use: a survey of UK neuro critical care practice. Anaesthesia 2006;61(11):1075–8.
10
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ANESTHETIC VAPORS (SEDA-27, 119; SEDA-28, 139; SEDA-29, 129; SEDA-30, 137)
HALOGENATED VAPORS
40 patients (2C). Malondialdehyde concen trations and protein carbonyl content were significantly higher and sulfhydryl groups significantly lower in those who received desflurane.
Desflurane
Susceptibility factors Genetic In a case of malignant hyperthermia there was a negative gradient between arterial and endtidal CO2 during anesthesia, which was used as a diagnostic and monitoring tool (3A).
Respiratory The effect of intravenous fentanyl given before thiopental induction on airway irritation caused by a stepwise increase in desflurane has been studied in 80 children aged 2–8 years in a doubleblind, randomized, placebo-controlled study (1C). Fentanyl reduced the incidence of airway irritation (cough 2.5% versus 43%; secretions 28% versus 83%; excitation 10% versus 83%; apnea 20% versus 65%). The mean expired desflurane concentration at which the first airway irritation symptom occurred was greater with fentanyl.
Smoking Cigarette smokers have a greater risk of respiratory complications during anesthesia than non-smokers, but it is not known to what extent the pungency of inhaled anesthetics contributes. Desflur ane and sevoflurane, the latter being more pungent, have been compared in 55 patients each (4C). There were no differences in the incidences of cough (five versus nine patients respectively), breath holding, lar yngospasm, or desaturation.
(SED-15, 1072; SEDA-30, 137)
Cytotoxicity Free radicals can trigger oxidative stress, leading to the production of malondialdehyde and protein carbonyl content, and the extent of oxidative status can be increased by volatile agents. The effects of sevoflurane+fentanyl, sevoflurane +nitrous oxide, desflurane+fentanyl, and desflurane+nitrous oxide together with pneumoperitoneum have been reported in Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03110-9 r 2009 Elsevier B.V. All rights reserved.
Management of adverse drug reactions In two studies the value of combining antie metic agents in treating postoperative nau sea and vomiting has been demonstrated. Intravenous dexamethasone and tropise tron reduced the incidence of postoperative nausea and vomiting by about 35% in a double-blind, randomized, placebo-controlled study in 320 patients after anesthesia with benzodiazepine premedication, propofol, rocuronium, desflurane in air/O2, and fen tanyl or sufentanil, followed by a contin uous infusion of remifentanil (5C). The two drugs had additive effects, although even in the combination group the incidence of nausea and vomiting was still unacceptably high.
217
218 In another randomized, double-blind study in 105 adults undergoing thyroidect omy the addition of propofol 0.5 mg/kg to tropisetron 5 mg improved its antiemetic effects after anesthesia with desflurane (6C) (17% versus 43% with tropisetron alone and 77% with placebo).
Isoflurane (SED-15, 1921; SEDA-30, 138) A Polish Expert Group for Chemical Hazards has suggested that the maximum admissible concentrations for isoflurane in places where it is used should be 32 mg/m3 (4 ppm), and that this limits should protect surgical staff from the adverse neurological, cardiovascular, respiratory, and irritant effects of isoflurane (7RS). Liver Isoflurane-associated hepatotoxicity has been reported (8A). A 68-year-old man developed fulminant fatal
hepatic necrosis 2 days after open cholecys tectomy under isoflurane anesthesia. He had greatly raised transaminases and bilirubin and a prolonged prothrombin time. Serological studies were negative for viral hepatitis. Postmortem examination showed centrilobu lar necrosis of the liver.
Sevoflurane
(SED-15, 3123; SEDA-28, 139; SEDA-29, 129; SEDA-30, 138)
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cardiovascular, respiratory, and irritant effects of sevoflurane (7RS). Cardiovascular The dysrhythmogenic properties of anesthetics are of major concern and there is as yet no safe anesthetic regimen for patients with a prolonged QT interval or those suspected to be at risk. However, electrophysiology experiments have shown that volatile anes thetics, such as sevoflurane, prolong the QT interval by inhibiting the repolarization phase of the action potential. The human ether-a-go-go related gene (HERG) chan nel appears to be involved in this process. A comparison of the effects of sevoflurane and propofol on the QT interval in guinea pigs has confirmed that sevoflurane pro longs the QT interval, and that propofol does not. Furthermore, sevoflurane inhib ited the outward tail currents in HERG channels expressed in Xenopus oocytes, whereas propofol had no effect (10E). In a blinded study in 20 women aged 38–51 years of ASA stages I and II, who were given sevoflurane for total abdominal hysterectomy, there were no significant changes between baseline and final QTc dispersion and between the low- and highfrequency components of heart rate varia bility, despite a significant increase was seen in the variability in RR interval, which was used as a measure of cardiac autonomic tone (11c). An 8-year-old boy with congenital long QT
Occupational exposure to anesthetic gases, such as sevoflurane, can be mitigated by the use of anesthetic gas extractors (9c). In the breathing areas around anesthesiologists mean exposure to sevoflurane without an extractor was 12 ppm. In those who worked with an extractor, exposure was 91% lower (1.1 ppm). There were also higher rates of general discomfort (62% versus 11%), nau sea (62% versus 0%), and headache (62% versus 0%) in the absence of an extractor. A Polish Expert Group for Chemical Hazards has suggested that the maximum admissible concentrations for sevoflurane in places where it is used should be 55 mg/m3 (7 ppm), and that this limits should protect surgical staff from the adverse neurological,
syndrome (LQT2) continued to have attacks of syncope despite nadolol 80 mg/day (12A). He was anesthetized with 2.8–3% sevoflurane for implantation of an internal cardioverter– defibrillator. After 20 minutes he had a run of multifocal ventricular extra beats followed by a spontaneously resolving episode of torsade de pointes lasting 5 seconds. A second episode caused hemodynamic compromise. The sevo flurane was withdrawn and propofol 5 mg/kg/ hour was given intravenously. The dysrhyth mias immediately resolved.
Despite the suggestive time course in this case the association of sevoflurane with torsade de pointes has been challenged (13r). Care is perhaps nevertheless indi cated when using sevoflurane in patients with congenital long QT syndrome (14r).
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Chapter 10
Nervous system A 2-year-old child, ASA grade 1, developed myoclonic jerks during anesthesia with sevoflurane (15A). A 23-year-old Taiwanese man with no history
of epilepsy had a generalized convulsion with a mild fever after 11 hours of anesthesia with sevoflurane anesthesia (16A). The episode resolved after aggressive management. Another 3 hours were required to complete the operation and the patient recovered uneventfully.
Sensory systems The effects of anesthetic agents on stapedius reflex thresholds and transient evoked otoacoustic emissions have been studied in 50 patients who were scheduled for operation and who had normal hearing (17c). Anesthesia was main tained with 70% nitrous oxide +30% oxygen, sevoflurane, desflurane, halothane, or intravenous propofol+sufentanil. Mida zolam significantly increased ipsilateral and contralateral stapedius reflex thresholds and reduced the wave reproducibility of the otoacoustic emissions. Propofol signifi cantly increased the stapedius reflex thresholds. The other anesthetic agents significantly increased only the contralat eral reflex thresholds, the largest effect being with sevoflurane and the smallest with halothane. The authors concluded that sevoflurane should not be used when it is necessary to measure stapedius reflex thresholds under general anesthesia. Psychological The effects of brief sevo flurane–nitrous oxide anesthesia on post operative cognition and behavior have been studied in 48 children aged 5–10 years undergoing anesthesia without premedica tion for multiple dental extractions and 48 control children (18c). Mean choice reaction time and psychomotor co-ordination were significantly impaired postoperatively but had recovered by 48 hours, although mea sures of variability suggested residual impairment. There was profound retrograde amnesia postoperatively and at 48 hours, but recognition memory was not impaired. Attention-seeking, tantrums, crying, and nightmares were more frequent in 8–20% of the children 1 week after the procedure.
219
Musculoskeletal A patient had two epi sodes of severe muscle rigidity, increased end-tidal CO2, and increased creatine phos phate kinase activity after sevoflurane anesthesia (19A). Genetic testing for the 17 known mutations associated with malignant hyperthermia was negative. Although the authors could not rule out malignant hyperthermia or other neuromuscular dis eases they suggested that this rare event may have been directly due to sevoflurane.
Trichloroethylene (SED-15, 3488; SEDA-28, 140; SEDA-29, 130; SEDA-30, 140) The health risks of trichloroethylene have been reviewed (20R). Respiratory Acute lung damage has been reported in a man who inhaled trichloro ethylene (21A). A 28-year-old man who cleaned tubes that had
been washed with trichloroethylene became unconscious with acute lung injury. ACT scan showed a ground-glass opacity in the left upper lobe. Bronchoalveolar lavage fluid contained alveolar macrophages, lymphocytes, and neutrophils. There were erythrocytes in the alveolar spaces in a lung biopsy and vacuolation of the cytoplasm of type 2 alveolar pneumocytes.
Nervous system Neurotoxicity from tri chloroethylene has again been reported (22A). A 32-year-old male drug addict had temporal
lobe seizures after “huffing” (i.e., voluntarily inhaling) trichloroethylene. He also developed cognitive dysfunction (with memory disorders in particular) and personality changes. These disorders had not been noticed by the patient’s wife before the last episode of inhalation. Four months later, the cognitive disorders had stabilized and he had had no further seizures.
The authors suggested that trichloro ethylene had had a selective effect on the temporal lobe. Skin Workers exposed to trichloro ethylene rarely have severe generalized skin disorders and accompanying hepatitis, which resemble drug hypersensitivity reactions. The
220 effects are distinct from solvent-induced irritating contact dermatitis. In a systematic review of the published literature (239 cases) 124 (52%) cases were classified as hyper sensitivity syndrome and 115 (48%) as erythema multiforme/Stevens–Johnson syn drome/toxic epidermal necrolysis (23M). The reports from Western industrialized coun tries were mostly published up to 1990, whereas cases from Asian industrializing countries appeared thereafter. The association between genetic poly morphisms of human leukocyte antigenDQ (HLA-DQ) and susceptibility to tri chloroethylene-induced severe generalized dermatitis has been investigated in a case– control study in 112 patients with severe generalized dermatitis and 142 healthy con trols exposed to trichloroethylene in the same workshop (24C). The frequencies of DQA1�0201 and 060101/0602 were 7.6% (17/224) and 16% (36/224) in cases, signifi cantly higher than in the exposed controls: 3.5% (10/284) and 7.0% (20/284). The frequencies of DQA1�0103 and 050101/ 0503/0505 were 5.8% (13/224) and 8.9% (20/224) in cases, significantly lower than in exposed controls: 11% (31/284) and 17% (49/284). Five codons of DQA1 (25, 41, 52, 54, and 69) showed significant differences between cases and controls. There were no significant differences in the frequencies of allelic genotypes of HLA-DQB1. In a similar study, the frequencies of HLA-DMA and HLA-DMB have been studied in 61 patients with trichloroethy lene-induced dermatitis and in 60 healthy controls (25C). The frequency of the HLA DMA�0101 allele was significantly higher in the patients than in the controls (71% versus 55%), as was the allele frequency of HLA DMA�0103 (12% versus 3.3%) and the ratio of �0102 homozygotes of HLA DMA�0102 (25% versus 8.2%). The ratio of �0102 heterozygotes of HLA-DMB�0101 was lower in the patients than in the controls. Tumorigenicity Different committees have reported that trichloroethylene is either “probably” (26S) or “reasonably anticipated to be” (27S) carcinogenic in humans. According to the National Toxicology Program “trichloroethylene is reasonably
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anticipated to be a human carcinogen based on limited evidence of carcinogenicity from studies in humans, sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors at multiple tissue sites in multiple species of experimen tal animals, and information suggesting [that it] acts through mechanisms that indicate it would [probably] cause cancer in humans.” The relative risks, standardized incidence ratios, and standardized mortality ratios from cohort studies and the odds ratios from case–control studies for four types of cancers—liver, liver and biliary tract, and kidney tumors, and non-Hodgkin’s lym phoma—have been reviewed (28RM). The main problems that beset a proper inter pretation of the data are (a) the relative sensitivity of cancer incidence and mortality data; (b) different classifications of lympho mas, including non-Hodgkin lymphoma; (c) differences in data and methods for assign ing trichloroethylene exposure status; and (d) different methods used for making causal inferences, including statistical approaches and meta-analyses. However, the overall data suggest that there are increased risks of cancers of the kidney, liver, and lymphatic systems in those who are occupationally exposed to trichloroethy lene, with typical relative risks of 1.5–2.0. In a meta-analysis of 14 occupational cohort and four case–control studies of workers exposed to trichloroethylene the summary relative risk estimates for non Hodgkin’s lymphoma from the cohort studies was 1.29 (95% CI ¼ 1.00, 1.66) for the total cohort and 1.59 (95% CI ¼ 1.21, 2.08) for the seven studies that identified a specific sub-cohort that had been exposed to trichloroethylene (29M). However, com parison of the relative risk estimates by trichloroethylene exposure did not indicate a dose–response effect. Case–control stu dies had a summary relative risk estimate of 1.39 (95% CI ¼ 0.62, 3.10). The interpreta tion of the results of this analysis was hampered by variability in results across the studies, limited assessments of expo sure, lack of supportive information from toxicological and mechanistic data, and the
General anesthetics and therapeutic gases
Chapter 10
absence of consistent findings. Although there was a modest positive association in the sub-cohort analysis, there was insuffi cient evidence to suggest a causal link between exposure to trichloroethylene and non-Hodgkin’s lymphoma. The carcinogenic effects of trichloroethy lene may be at least partly medicated by its metabolites dichloroacetic acid and trichlor oacetic acid (30E). A meta-analysis of epidemiological stu dies of occupational exposure to trichlor oethylene has shown no association with either multiple myeloma or leukemia (31M). Teratogenicity The risks of congenital heart defects after exposure to trichloroethy lene have been analyzed by a systematic review of the epidemiological data and animal studies (32M). No single process was clearly affected by trichloroethylene, provid ing support that gestational exposure does not increase the prevalence of congenital heart defects. Application of Bradford Hill’s causality guidelines showed no causal link.
OTHER VAPORS
221
by arm weakness, leg paraplegia, and neuro genic bladder (33A). He had hyperhomo cysteinemia and a low serum vitamin B12 concentration. There was a polymorphism in the MTHFR gene associated with the thermolabile isoform of the 5,10-methylene tetrahydrofolate reductase enzyme, which explained the myelopathy after exposure to nitrous oxide. Therapy with folic acid and vitamin B12 resolved the neurological symptoms. Drug abuse In a 33-year-old man nitrous oxide abuse caused vitamin B12 deficiency, which resulted in bizarre behavior and delusions, which responded to treatment with intramuscular cobalamin (34A). Management of adverse drug reactions Occupational exposure to anesthetic gases, such as nitrous oxide, can be mitigated by the use of anesthetic gas extractors (9c). In the breathing areas around anesthesiologists mean exposure to nitrous oxide without an extractor was 423 ppm. In those who worked with an extractor, exposure was 94% lower (25 ppm). There were also higher rates of general discomfort (62% versus 11%), nausea (62% versus 0%), and headache (62% versus 0%) in the absence of an extractor.
Nitrous oxide
(SED-15, 2550; SEDA28, 140; SEDA-29, 131; SEDA-30, 140)
Observational studies The adverse effects of a 50% nitrous oxide/oxygen mixture have been studied in a 4-year prospective survey of 35942 data sheets received from 191 French hospital pediatric units (82%) and adult units (18%), of which 35828 were sufficiently complete to be used. There were 1581 (4.4%) adverse events reported on 1384 data sheets, mostly gastrointestinal and neuropsychiatric disorders (86%). The main factors associated with adverse events were age, concomitant drugs, and longer duration of inhalation. Of 27 (0.08%) serious adverse events, only 9 (0.03%) were possibly attributable to the mixture. Nervous system A patient who received nitrous oxide on two occasions in 8 weeks developed a diffuse myelopathy, characterized
INTRAVENOUS AGENTS: NON-BARBITURATE ANESTHETICS Etomidate (SED-15, 1302; SEDA-30, 140) Nervous system Myoclonic movements and pain on injection are common during induction of anesthesia with etomidate. The bispectral index is commonly used to judge the level of anesthesia and provides a single dimensionless number derived from a Fourier transform of the electroencephalogram. A value of 0 indicates electroencephalographic silence, 100 is the expected value in a fully awake individual, and values between 40 and 60 are considered appropriate during general anesthesia. Electromyographic activity of the
222 facial muscles is one of the signals used by the bispectral index algorithm. Changes in the bispectral index have been documented in a patient with involuntary movements of the facial muscles during a severe episode of etomidate-induced myoclonus (35A). A 51-year-old man with no personal or family
history of epilepsy underwent general anesthe sia for excision of an anal polyp. Premedica tion consisted of oral midazolam. Anesthesia was induced with intravenous fentanyl fol lowed by an infusion of etomidate 5 mg/minute to a total of 20 mg. Shortly after losing his response to verbal commands, he started to have twitching of the muscles around the mouth, followed by tonic-clonic movements of the arms and legs. The bispectral index, which had fallen to a minimum of 40, increased rapidly to above 70. The involuntary movements ceased after an intravenous bolus of propofol 70 mg. Anesthesia was then main tained with nitrous oxide and sevoflurane. Recovery was uneventful and he had no recall of any of the events.
Myoclonus induced by etomidate appears to be different from epilepsy, as it is not associated with seizure-like electro encephalographic activity (36c). In this case, when the movements were terminated with a bolus injection of propofol, the bispectral index rapidly fell to a value consistent with anesthesia. In contrast to previous studies in which changes in bispectral index were investigated after induction with etomidate, this patient was not paralysed and devel oped myoclonic movements soon after losing consciousness. The analgesic properties and in particular the inhibitory effects of etomidate on spinal cord neuronal responses to noxious stimuli have been investigated in rats, which were anesthetized with isoflurane (37E). Lami nectomy was performed to record single unit activity. Lumbar neuronal responses to noxious thermal stimulation of the hindpaw were recorded before and every 2 minutes after administration of etomidate. The responses at peak effect of etomidate were reduced to 36% of the control response, depending on the dose (0.125, 0.25, 0.5, 1, and 2 mg/kg). The responses usually recovered within 10 minutes after injection. There were similar effects in decerebrate isoflurane-free rats. The authors concluded
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that etomidate depresses spinal cord neu ronal responses to noxious stimulation and that this might be a possible mechanism by which etomidate produces analgesia.
Ketamine (SED-15, 1964; SEDA-28, 141; SEDA-29, 131; SEDA-30, 141) Nervous system Ketamine potentiates intravenous or epidural morphine analgesia. The effect of an infusion of a very low dose of ketamine on acute and long-term postthoracotomy pain has been studied in 49 patients who were randomly assigned to one of two regimens: continuous epidural infusion of ropivacaine+morphine for 2 days, along with an intravenous infusion of ketamine 0.05 mg/kg/hour or placebo for 3 days (38c). Postoperative visual analog scale scores and numerical rating scale scores 1 and 3 months after surgery were lower after ketamine. Three months after surgery, more control patients were taking pain medications.
Propofol
(SED-15, 2945; SEDA-28, 142; SEDA-29, 132; SEDA-30, 142) Cardiovascular Because of its fast onset and offset of hypnotic action and its short, context-sensitive half-life, propofol is an attractive intravenous anesthetic for induction and maintenance of anesthesia. Several aspects of its interactions with the cardiovascular system in patients with left ventricular dysfunction have been reviewed (39R). Propofol reduces arterial blood pressure, mainly by reducing sympathetic tone, vascular resistance, and preload, and not by impairing myocardial contractility. Although it has negative inotropic effects, partly mediated by reduced uptake of calcium into the sarcoplasmic reticulum, they do not appear to be clinically important. It is not clear, however, how propofol affects cardiovascular function in patients with severe left ventricular dysfunction. Experiments in rodents have not shown any effects in compensated or congenital hypertrophic cardiomyopathy, and a study on left ventricular trabeculae from pigs with pacing-induced congestive heart failure suggested that the myocardial
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depressive effects of propofol might be more pronounced in the presence of left ventricular dysfunction than in healthy hearts (40E). In dogs with dilated cardiomyopathy induced by continuous pacing at 240 Hz for up to 3 weeks, propofol reduced left ventricular preload, afterload, and regional chamber stiffness, caused a dose-related direct negative inotropic effect, and impaired early diastolic left ventricular filling (41E). The protective effects of propofol in ischemia/reperfusion injury have been reviewed. Propofol inhibits specific subu nits of KATP channels, but only in con centrations 5–15 times higher than those encountered during clinical anesthesia (42R). Protection may also be provided by scavenging of free oxygen radicals, reduced disulfide bonding in proteins, and inhibition of lipid peroxidation. Additional protective effects may be related to inhibi tion of the mitochondrial permeability transition pore, which represents opening of non-specific pores in the inner mito chondrial membrane under conditions of increased oxidative stress. The authors concluded that propofol causes only mini mal myocardial depression in the healthy heart at clinically relevant concentrations, but that the risk of cardiac depression may be increased in the failing heart. It should therefore be administered slowly, in order to allow the cardiovascular system to compensate for the associated hemody namic changes. For intravenous anesthesia, propofol should be combined with opioids, which have relatively few cardiovascular adverse effects and also protect against ischemia/reperfusion injury. Respiratory General anesthesia can cause airway compromise. In a prospective study in nine infants undergoing elective MRI scanning of the brain, spin echo magnetic resonance images of the airways were acquired during different stages of propofol anesthesia (80 and 240 mg/kg/minute) with and without 10 mmHg continuous positive airway pressure (43c). At each anatomical level, airway caliber fell as the depth of propofol anesthesia increase, an effect that was completely reversed by continuous
223
positive airway pressure. This study has highlighted the need for appropriate airway support as the depth of anesthesia increases, even if spontaneous ventilation is maintained. Nervous system There is a debate about whether propofol has proconvulsant or anticonvulsant effects and whether it should be used in patients with epilepsy. The effects of intravenous propofol on the electroencephalogram have been assessed prospectively in children with epilepsy (44c). There were no seizure-like phenom ena during and after propofol sedation. Immediately after withdrawal of propofol, the characteristic electroencephalographic patterns in children with epilepsy consisted of transient increased beta wave activity (23/25 children) and suppression of pre existing theta rhythms (11/16 children). In addition, spike-wave patterns were sup pressed after propofol sedation (16/18 children with epilepsy). In 25 children with learning difficulties there was a transient increase in beta wave activity and there was suppression of theta rhythms in 11 of 12 children. The results of this study have supported the concept that propofol has anticonvulsant properties. In neuroanesthesia propofol has advan tages over volatile anesthetics (45R). The authors regard propofol as first-choice anesthetic, because it is associated with lower intracranial pressure and cerebral swelling than volatile anesthetics in patients with brain tumors undergoing craniotomy, hardly interferes with somatosensory, audi tory and motor evoked potentials, and provides excellent and predictable recovery conditions as well as minimal postoperative adverse effects. Similar to cardiovascular protection, the potential neuroprotective effect of propofol may be mediated by antioxidant effects. Metabolism The propofol infusion syndrome is the commonest cause of death directly related to the use of propofol, and deaths associated with the use of propofol for sedation have been reviewed (46M). All reports of deaths after sedation with pro pofol in children and adults submitted to
224 the Food and Drug Administration (FDA) and entered into its post-marketing drug safety database were considered, as were published reports and studies. The propofol infusion syndrome was defined as metabolic acidosis and/or rhabdomyolysis with pro gressive myocardial failure. Between 1989 and April 2005, the Adverse Event Report ing System of the FDA received reports of 21 patients aged 16 years or under and 68 patients aged over 16 years who died after administration of propofol for non-proce dural sedation. The most frequent symp toms were progressive cardiac dysfunction/ failure (bradycardia, cardiac failure, “cardio vascular collapse”, dysrhythmias, and cardiac arrest), metabolic acidosis, hypoten sion, and rhabdomyolysis. Additional symp toms described in the adults were renal failure, respiratory failure/adult respiratory distress syndrome, persistent sedation, hyperthermia/fever, hypertriglyceridemia, multiorgan failure, liver dysfunction, tre mors/weakness/polyneuropathy/movement disorders in five, sepsis in five, hepatic failure in four, and hyperkalemia. However, the specificity of the latter symptoms for propofol infusion syndrome is questionable. The authors concluded that some adult deaths and a large number of children’s deaths reported in the post-marketing drug safety database of the FDA have a striking similarity in clinical characteristics, course of illness, and propofol dose and duration to published reports and studies of the propofol infusion syndrome. This review and the many published case reports must lead to the recommendation that propofol in higher doses, in higher concentrations, and for longer durations must be avoided in both children and adults. Doses of propofol should be kept as low as effectively possible, and regular hemodynamic and blood gas monitoring is necessary in patients who are sedated with propofol, in order to detect early signs of cardiovascular failure and lactic acidosis. As previously recommended by the American College of Critical Care Medicine (47S), alternative sedative agents should be con sidered for patients who develop increasing requirements for vasopressors or inotropes
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or cardiac failure during high-dose propofol infusion. The propofol infusion syndrome has been reported in a young patient with traumatic brain injury, which is a suscept ibility factor, as high doses are often required to achieve a satisfactory degree of sedation and/or to control raised intra cerebral pressure (48A). A 21-year-old man with traumatic brain injury
was given high doses of propofol for sedation and control of intracranial pressure, combined with vasopressor therapy to maintain a cere bral perfusion pressure above 60 mmHg. He developed a significant metabolic acidosis with a lactic acid concentration of 11 mmol/l. Exploratory abdominal laparotomy showed no traumatic injury. During the procedure, the propofol infusion was discontinued and the lactic acidosis improved. An echocardiogram showed severe left ventricular dysfunction and cardiomyopathy, which resolved within 19 days.
The authors thought that a combination of high-dose propofol and catecholamines had been responsible for the lactic acidosis in this case. In addition, the use of intravenous inotropes may aggravate lactic acidosis or even trigger the propofol infu sion syndrome. In this case, early diagnosis and immediate withdrawal of propofol may have contributed to the complete reversal of symptoms and the favorable outcome. Liver Postoperative serum aspartate transaminase, alanine transaminase, and lactate dehydrogenase activities increased transiently after the use of propofol in 160 patients undergoing elective coronary artery surgery, more so than in 160 patients who were given sevoflurane (49c). Lactation The transfer of propofol into breast milk has been studied in five women (50c). They were premedicated with mid azolam before induction of anesthesia with propofol and fentanyl. Anesthesia was main tained with volatile anesthetics. During 24 hours of milk collection, 0.004–0.082% of the dose of propofol was excreted into the milk. Although evidence is scarce, lactating women are frequently advised to pump and discard their milk for 24 hours after the
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operations requiring general anesthesia. However, based on these results, the authors concluded that interrupting breast-feeding in this way is not justified. Susceptibility factors Age The effects of age on sedation induced by propofol and midazolam have been studied in patients under and over 65 years undergoing cardi oversion in a randomized study (51C). Mean induction times were similar. However, mean recovery time was shorter in those who received propofol and in patients under 65 years. Older participants needed less medication. There were no hemodynamic differences between the groups, but desa turation was higher in the patients who received midazolam. Hemorrhage Four patients with advanced cirrhosis became hemodynamically unstable as a result of massive blood loss during surgery; this was associated with increases in total propofol (twofold) and unbound pro pofol (fourfold) (52c). All were resuscitated within 60 minutes. Propofol is highly bound to plasma albumin, erythrocytes, and lipo proteins, and the unbound fraction is usually under 3%. Changes in protein binding and reduced renal and hepatic blood flow during shock can alter the clearance of propofol. Drug formulations There has been a report of complications associated with propofol, owing to malfunction of a com mon drug infusion pump (53A). The syringe saddle was missing and allowed the syringe barrel to contact the pump case, which reduced outward displacement of the syr inge clamp. The infusion pump then falsely detected a smaller syringe size and conse quently delivered an increased infusion rate, resulting in propofol overdose. More commonly, an incorrectly mounted syringe may increase outward displacement of the syringe clamp, so that the infusion pump falsely detects a larger syringe size; this results in a reduced infusion rate. Generic propofol (with a sulfite additive) and Diprivan have been compared in a randomized, double-blind study in 60
225
women undergoing abdominal hysterectomy (54c). The mean drug doses adjusted for weight and time were similar, and similar blood propofol concentrations were needed to adjust the depth of anesthesia to a bispectral index of 50–65. Propofol is lipid-soluble and is formu lated as a water-in-oil emulsion, which has drawbacks, such as injection pain and micro-organism contamination. A lipid-free formulation of propofol became available in India in 2006 (Cleofol 1%, Themis Pharmaceuticals, Mumbai). However, sev eral adverse effects of this formulation, which contained thiomersal as a preserva tive, were reported, including extravasation (55A) and acute venous thrombosis (56A). A 48-year-old woman was given Cleofol 10 ml
premixed with lidocaine via a cannula in the most prominent vein on the dorsum of the left hand. In the postanesthesia care unit, extra vasation was observed. She complained of severe pain in her left hand. The skin was erythematous and swollen. The radial pulse was easily palpable. Her left arm was raised and subcutaneous hyaluronidase was injected. Over the next 4 hours the edema increased and the hand was swollen, tense, and cyanotic, with delayed capillary refill. The skin of the dorsum of the left hand was incised, the tissues were flushed out with 500 ml of isotonic saline, and drains were inserted for 24 hours. A layer of betadine soaked gauge was applied to the wound. Four weeks later, the site of extra vasation had healed without any undue sequelae. A 55-year-old woman with well-controlled hypertension was given Cleofol 1.5 mg/kg through an intravenous cannula in the left forearm. At the time of injection she com plained of severe pain in the forearm and arm, which subsided after flushing the cannula with isotonic saline. Two subsequent injections of propofol also caused severe pain. Following the fourth bolus of propofol the patient awoke with excruciating pain in the limb. The super ficial veins of the left forearm became promi nent, tender, and cord-like and the peripheral blood oxygen saturation monitored in the left index finger fell to 78–80%. The left forearm and hand were swollen, dusky blue, and cold. There was retrograde flow of blood into the intravenous giving set. The intravenous infu sion in the left forearm was discontinued and a new line started in the right hand. Efforts to flush the cannula in the left forearm were unsuccessful, but a 5-cm blood clot was aspi rated. Doppler examination showed blockage of
226 the brachial vein in the left antecubital fossa and compression of the brachial artery by grossly engorged brachial veins.
In the second case the reduction in peripheral blood oxygen saturation in the affected limb was probably related to compression of brachial artery by engorged brachial veins and by edema due to deep vein obstruction. Drug administration route Accidental injection of propofol and remifentanil into the cerebroventricular compartment has been reported (57A). A 51-year-old patient was accidentally given
remifentanil 150 mg and 10 ml of propofol 1% through an intracerebroventricular totally implantable access port placed in the right infraclavicular region, which was mistakenly thought to be an intravenous line. Severe pain in the head and neck caused the mistake to be discovered rapidly, and 20 ml of a mixture of cerebrospinal fluid and the anesthetic drugs were aspirated from the implantable access port. There were no apparent adverse neuro logical sequelae.
Management of adverse drug reactions Pain on injection with propofol occurs in about 70% of patients (SEDA-30, 143), and there have been many studies, with varying success, of ways of minimizing the pain. Low-dose ketamine seems promising in reducing injection pain and in mitigating the respiratory depression and hypotension associated with propofol (58c). Low doses
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of ketamine have been compared with saline and lidocaine in 240 patients in order to establish the optimal dose for prevention of pain after propofol injection (59C). Ketamine 100 mg/kg immediately before propofol injection was the optimal dose and timing to reduce propofol-induced pain on injection.
INTRAVENOUS AGENTS: BARBITURATE ANESTHETICS Thiopental sodium
(SED-15, 3395;
SEDA-30, 146) Monitoring therapy There has been a survey of how thiopental was used in UK neurosurgery critical care units (60A). It was used in 23 out of 26 participating units, and 14 had a protocol or guidelines of its use. Cerebral monitoring was used to guide dosage in 17 units. Twenty units delayed brain stem testing when patients had had thiopental, two would not perform tests at all, and one incorporated cerebral angiography into their protocol. This survey demonstrates a lack of uniform management regimens for brain stem testing after the administration of thiopental. There is clearly a need to clarify when brain stem testing should be performed in such cases, if at all.
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