If we ask ourselves “what is the scientific definition of anesthesia?”, the three golden rules usually come to mind. However, the principle of “loss of consciousness, analgesia, and muscle relaxation” is more like a descriptive definition with a loose boundary. Until the past 2 years, despite increased knowledge in anesthesiology, we could not answer the following two simple questions in a precise manner: “What happens in the brain and body during anesthesia?” and “Are there any adverse effects of anesthesia during and after general anesthesia?” These questions were raised by the observation of awareness during anesthesia, and surgical stress syndrome occurring remote from the time and place of the operation. However, anesthesia per se cannot prevent the occurrence of these phenomena. Surgery is innately invasive procedure, although for good purposes, and can cause potentially lethal stress responses. Surgery has been revolutionized by continued evolution in the knowledge and techniques of anesthesiology, which has reduced stress and improved the survival rate. However, anesthesiologists still lack a theory to answer the above two questions, in order to optimize the outcome of anesthesia.

Some controversy remains with regard to hemodynamic, end-tidal CO₂ and stress management during anesthesia. We were all trained to take it as granted that to maintain a relative hypertension equals to effective cardiac function and tissue perfusion and maintain minor hypocarbia routinely to avoid hypercarbia-related myocardial toxicity during anesthesia. Hypertension with tachycardia usually cause low cardiac output and tissue perfusion, and permissive hypercarbia protects the lungs from injury, preserves respiratory chemoreceptor function, enhances respiratory drive, accelerates opioid clearance from the brain, reduces blood viscosity, and increases cardiac output. These controversies continue to confuse anesthesiologists due to lack of a practical theory to connect surgery-induced stress responses with anesthesia.

Most anesthetics exert their effects as N-methyl-d-aspartate receptor antagonists and γ-aminobutyric acid receptor agonists, which results in widespread neuroapoptosis in the central nervous system. These results have been reproduced in many species using different combinations of anesthetics in common clinical use. For example, the combination of sevoflurane with propofol resulted in robust neuroapoptosis in the neonatal mouse brain.¹Anesthesia-induced cognitive impairment has been observed in developing²and aging³ brain. Besides the receptor theory, the neuroinflammation related cytokines, such as the IL-1 and IL-6, induced by surgical stress during anesthesia is another important factor2, 4, 5, 6, 7, 8, 9, 10 in post-anesthesia cognitive deficiency. Although the results obtained from current clinical studies were criticized with overtly subjective and lack of strong association statistically, the International Anesthesia Research Society and the US Food and Drug Administration have released a statement about anesthetic-related neurotoxicity for parents of pediatric surgery patients, in the Smart Tots website (http://www.smarttots.org/aboutus.drRoizensAdvice.html).

Before 2004, most studies on anesthesia for cancer surgery focused on preoperative assessment, monitoring, and intraoperative support.¹¹ The first evidence that fentanyl extends cancer survival time came in 2004,¹² and subsequently, many studies have demonstrated, although not conclusively, that most common anesthesia techniques differentially affect cancer recurrence in patients undergoing surgery.13, 14, 15, 16, 17 Major tumor-promoting factors, including immunosuppression, stimulation of angiogenesis, and dissemination of residual cancer cells,¹⁷ could be attributed to surgical inflammation, anesthetics, and inadvertent anesthesia management during surgery resulted in inadequate stress management. In this issue of Acta Anaesthesiologica Taiwanica, Professor Ma from Imperial College London shares his experience on inhalation anesthetics and tumor progression, and he has demonstrated that isoflurane enhances renal cancer growth via the hypoxia-inducible factor-1 signaling pathway.¹⁸ Besides tumor recurrence,¹⁹ Professor Ma is also interested in anesthesia-related cognitive dysfunction,20, 21, 22, 23, 24 neuroapoptosis25, 26, 27 and early memory decline.28, 29 Therefore, the previous two unanswered questions return here, and I believe that many researchers might have same question: “Is it possible to devise a common theory to explain all these anesthesia-related events?”

The recently discovered stress repair mechanism (SRM) provides a unified theory of anesthesia, analgesia and allostasis, which offers a possible explanation for the anesthesia-related issues above, and enables modification of current anesthetic techniques to optimize surgical outcome.30, 31 The stress theory was postulated in 1951 by Hans Selye, and it inspired intensive research on the stress mechanism, but it eventually failed to link stress and surgical outcome. The first description of SRM was supported by a vast amount of fresh evidence, in which two major components, capillary gate and tissue repair, were included and the vascular endothelium plays a pivotal role between the two. As the sympathetic nervous system is activated, the capillary gate closes, which is manifested by Von Willebrand factor release from the vascular endothelium. This subsequently increases factor VIII activity, activates thrombin, increases blood viscosity and coagulation, and thus decreases cardiac efficiency, and increases blood pressure and heart rate. Increased parasympathetic nervous system activity opens the capillary gate, which is manifested by release of nitric oxide from the vascular endothelium to inactivate thrombin. This subsequently decreases blood viscosity, increase cardiac efficiency, and reduces blood pressure and heart rate. Both the capillary gate and tissue repair components can be induced by surgical stress; however, both anesthesia and analgesia can suppress the capillary-gate-related stress via the cognitive and spinal pathways, respectively. The mechanism involved in surgery-induced tissue repair stress remains unresolved.30, 31However, both the cognitive and spinal pathways during anesthesia confer suppressive effects on the surgical stress and related positive feedback loop to the point for survive. Therefore, the surgical outcome can be substantially and continuously boosted as long as the synergistic effect of anesthesia and analgesia is carefully maintained throughout surgery, whereas the capillary gate mechanism and surgical-stress-related feedback loop are attenuated.

Thrombin is a universal enzyme involved in extracellular energy transformation. It utilizes ATP for cellular energy production and enzymatic activity related to inflammation, platelet activation, angiogenesis, chemokine and cytokine release, and is regulated by the capillary gate mechanism (sympathetic and parasympathetic nervous systems) and tissue repair stress induced by surgical stimuli. The generation of thrombin during anesthesia could therefore contribute to apoptosis and progression of malignancy through oxidative stress. Thrombin also regulates the balance between soluble and insoluble fibrin, which subsequently controls the systolic laminar flow, capillary flow, capillary hemostasis, systolic turbulent resistance and lateral force, immune response, and platelet activation and participation in inflammatory responses. Upregulated inflammatory mediators such as chemokines and cytokines may further lead to blood–brain barrier abnormality and subsequent neurotoxicity, including cognitive dysfunction.30, 31 These cytokine- and chemokine-mediated defects in the blood–brain barrier have been observed in an acute renal injury model in our laboratory (manuscript in submission). In addition, we have studied the role of platelets under surgical stress and found that platelets might also play a pivotal role in the vascular endothelium, in which the reciprocal mutual regulation between platelets and endothelium could be an novel central feature of the SRM (patent in application).

Although the SRM appears complex and roughly drafted, it is still a theory that could bridge the gap between anesthesia, surgical stress and recently observed adverse effects. The SRM also sheds light on the mechanism of surgical stress during anesthesia and could provide a basis for modification of anesthesia techniques to optimize surgical outcome. However, further investigation is needed to test the SRM theory in order to provide a novel way to resolve the problems such as cognitive dysfunction and malignancy.