Time to be "aware" of the gender difference

Article review on the impact of female sex on awareness, depth and emergence study 

Accidental awareness under anaesthesia (AAGA) is a nightmare not only for the patients but also for the anaesthetist and hospital. Accidental awareness and subsequent post-operative recall are estimated at approximately 0.1%-0.2%, with higher in obstetric cases (0.4%)¹. Despite its low incidence, the negative impact on patients and anaesthetists is invariably large and often leads to medical litigation. The experience of hearing and recalling the event during the surgery is deeply traumatising to the patient, with 71% of patients having post-traumatic stress disorder². Several risk factors have been identified in awareness under anaesthesia. Since the introduction of processed EEG in practice in 1992, this has changed the depth of anaesthesia monitoring entirely. The Association of Anaesthesia has published guidelines specifically to ensure the safe practice of TIVA⁹ to mitigate the effects of AAGA.

One risk factor of AAGA that is considered unworthy of comprehensive discussion is gender difference. Gender difference is a known subject to different responses in anaesthesia, for example, the incidence of post-operative nausea and vomiting (PONV), opioid response, sensitivity to anaesthesia and delirium, etc. Female gender is an independent risk factor for AAGA. Gender alone is not a common consideration in drug information provision and therapeutic effect recommendations in pharmacology. The lack of understanding of the relation of gender difference to anaesthesia might be the missing piece of the puzzle. This, unfortunately, leads to females constantly being subjected to a lighter stage of anaesthesia and awareness.

Meta-analysis and systemic review:

A recently published systemic review on the impact of sex differences on the incidence of awareness, depth of anaesthesia, and emergence³ might contain the answer we have been looking for. The authors defined the terminology’ awareness’ as 1) post-operative recall or 2) connected consciousness (intra-operative responsiveness to command after anaesthesia). Sixty-four (64) studies fulfilled the inclusion criteria after screening 19749 studies. The study amounted to 98243 participants: 53143 females and 45100 males. Thirty-one (31) studies reported awareness of post-operative recall in the female and male groups. Females were significantly associated with confirmed awareness and post-operative recall events. Females also experienced a higher mean rate of connected consciousness in three studies that assessed consciousness using the isolated forearm technique intra-op. In the context of emergence, the female has a faster mean time to eyes and obey the commands, although the time to extubation did not differ. Eighteen (18) studies included the data on depth of anaesthesia monitoring. Although the end-tidal agent concentration to prevent somatic or purposeful response did not differ between males and females. One of the studies in the processed-EEG group found that females have higher p-EEG readings in the background of similar end-tidal anaesthetic agent concentrations. A higher dose of Propofol was also required to achieve deep anaesthesia in the female group.

Discussion:

Subsequently, the authors provided several reasons for the outcomes found in this study. One factor that has been overlooked for a long time is the gender difference in pharmacokinetic and pharmacodynamic profiles. In general, the female has lower sensitivity towards Propofol than males, and this is supported by evidence of higher Propofol requirement to lose consciousness and to maintain anesthesia⁴. During emergence, the study demonstrated that plasma concentration of Propofol declined more rapidly in females, and they woke up faster than male⁵. This is the consequence of higher Propofol metabolism in females. Therefore, more Propofol is required to maintain the depth of anaesthesia eventually. If given the same Propofol dose per body weight to both genders, females were found to have a lower plasma Propofol concentration⁶. The high metabolism of Propofol in females is due to variations in Cytochrome P450 (CYP450).

The CYP450 is a collective system of enzymes responsible for phase 1 drug metabolism. In general, the female has the higher activity of sub-enzyme CYP3A4 and CYP2B6 within the CYP450 system⁷; these enzymes are responsible for the oxidisation of Propofol. In addition, the female has 20-30% greater sensitivity to muscle relaxant effects of Rocuronium, Vecuronium and Pancuronium than male⁴. After placing every bit and piece into the puzzle (lower sensitivity to Propofol and higher sensitivity to paralysis agent), the reason for higher AAGA in females is now more legitimate than before. Apart from that, other physiological differences in females (cardiac output, hepatic perfusion, body fat composition and volume of distribution) have been suggested, too, albeit the extent of it remains questionable. The female sex hormone, in particular Oestrogen, is thought to play a role in the modulation of anaesthesia. Oestrogen appears to suppress GABA-A inhibition in the hippocampus and promote excitation on the cerebral cortex and cerebellum⁸. Oestrogen also potentiates Glutamate (a primary excitatory neurotransmitter) binding to N-methyl D-aspartate receptors⁸. The findings on the female sex hormone effect justified the question of ‘why’ pregnant mothers, a group with physiologically higher Oestrogen and Progesterone levels, have a higher risk of AAGA in NAP5.

Comment:

This meta-analysis is comprehensive in geographical distribution from various continents like Europe (22/64), Asia (22/64) and North America (11/64). The study included 4 multinational studies, although 3 were just observational studies. The majority of the studies clearly mentioned the specific anaesthetic protocol. For risk of bias assessment, 52/64 were considered good quality studies, 9 were regarded as fair with some concerns, and only 3 studies were graded as poor. Unfortunately, significant numbers of studies (407) were not included due to a lack of sex stratification of the outcomes. Should these data be available for analysis, the power of the study could have been better. Future research should focus more on good-quality RCTs involving multinational populations with sex-stratified outcomes. The use of the TCI algorithm with target effect-site concentration was found to better fit females than males in one study⁵. This finding should be tested again on a larger group sample.

Conclusion:

The fact that the female gender has a higher risk of AAGA could be the sequel of ‘under-dosing’ all the time by failing to appreciate the difference in gender-specific pharmacokinetic and pharmacodynamic profiles. This study serves as an advisory to everyone that gender differences do exist in the AAGA context. 

No conflict of interest declared in writing this article. 

Author

•  Dr. Kean Seng Cheah, Clinical fellow Anaesthetist. MBBS (Malaysia), FCAI (Ireland). Addenbrooke’s Hospital, Cambridge.

References:

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