Anesthesia Control: A Personal Opinion

Many progresses have been done in anesthesia during the last three decades. Most of them have been done for the intravenous anesthesia delivery. The laringela msk and related developed devices, like Propofol, and Computer-driven anesthetics procedures, have changed the way to deliver anesthesia, the approach to a faster recovery and a shorter hospital stay and promoting a great increase in daily surgery procedures and cutting down the hospitalization costs [1-5].


Introduction
Many progresses have been done in anesthesia during the last three decades. Most of them have been done for the intravenous anesthesia delivery. The laringela msk and related developed devices, like Propofol, and Computer-driven anesthetics procedures, have changed the way to deliver anesthesia, the approach to a faster recovery and a shorter hospital stay and promoting a great increase in daily surgery procedures and cutting down the hospitalization costs [1][2][3][4][5].
What it is not under a total control by anesthesiologists is the anesthesia itself, even though very important changes in the control of its levels has certainly been done. Anesthetists still don't have a secure and reliable way to understand which is the real level of anesthesia. There is still a lack in anesthesia delivery devices availability and in monitoring the real effects of anesthetic drugs [6]. This is not totally true for the use of halogenates in gas-driven hypnosis and anesthesia level control, where new gas time and dosages delivery concepts have been added to the MAC definition.

Discussion
The most important intraoperative or perioperative risks for a patient receiving anesthesia are well defined: A. Respiratory Depression both at induction of anesthesia and after the end of surgical procedure B. Intra operatory awakening C. Hemodynamic instability D. Delayed or missed recovery from anesthesia E. Late recurarization or missed decurarization Even late complications can be present, including: A. Vomiting B. Neurological depressed or not controlled activity, especially in neonate and elder patients or after complicated procedures C. Acute or late pulmonary damages (ALI or chronic pulmonary disease missed control) D. Immediate or late infections due to intra operatory ventilation During the last decades, many studies and research have been done to define a feasible clinical and instrumental way to have the greatest possible control over the hypnotic drugs and to recognize the signs indicating the depth of the anesthetic condition. The several changes in the definition of " Anesthesia" during the last four decades show us how the research in this field has been considered as a starting point to understand what we do when we are giving anesthesia and how we do it [7][8][9][10].
In 1981 Pinsker asserted that: "Anesthesia is defined as a combination of acts tending to get a status of A. Unconsciousness B. Paralysis

C. Stress Response Modulation"
In 1996, Barash defined "Anesthesia" as: "A reversible clinical status, inducted from drugs depressing central nervous system, ascending and descending it , that produces a lack of response and perception to all the external stimuli". In a few words, anesthetists can and must know in real time, which is the level of anesthesia and how to change it, if needed, closing a loop, considering the most of covariates data in their knowledge. Tachycardia and hypertension are not considered enough to define deep anesthesia, especially when a combination of volatile agents and opioid drugs is in use.
Even EEG response is not reliable, in many of its forms, since we still don't know very well the anesthetic mechanism defining the anesthetic status; this is more understandable when we consider the neural species variability and the not well known function of premature, neonatal, and elderly brain. SEMG (Surface electromiography can give a good panoramic of the decurarizazion (an increase of 30% from the basal value is acceptable) but doesn't give us any other data.
The BIS analysis (Bi-spectral Index) is not totally adequate to give a satisfactory indication about the depth of anesthesia since it is a number, and in 2018 it is not acceptable to indicate a condition with numbers; we need and must analyze the decadence or increase of the slope curves obtained analyzing specific data with a Fast Fourier Analysis FFA.. It is evident that a so high number of devices to control the anesthetic levels and its numerous covariables shows the importance of the problem and the difficulties to define an accurate and uniform way to control anesthesia [21][22][23][24][25][26].
A change was needed and this change came from the late 1989 early 1990, when the problem was studied from a different point of view i.e. not considering the results of anesthesia looking at clinical data, but trying to understand how to give the exact amount of drug to patients in order to reach a better defined effects.
It was evident that a second order pharmacodinamicpharmacokietic model was not enough therefore Shafer and Varvel (TCI Model) and Kern (CACI)Model) developed a different mathematical algorithm to create a theoretical third compartment, a depth compartment, to equilibrate the drugs action at Bio-phase. With the term Bio-phase we identify the receptorial activity and its clinical real time anesthetic drug consumption.
It is a combination of A. Pharmacodinamic phase : relationship between dose of drug administered and plasmatic concentration B. Pharmacokinetic Phase : relationship between drug administered dosage, plasmatic concentration, and clinical effect

This is a TIVA model
The Bio-phase or Site Effect is defined as the relationship between plasmatic therapeutical concentration and clinical effects. It is defined with an elimination constant value called "K0" that gives the exact theoretical amount of drugs acting in real time on the receptor

This is a TCI Model
It is not the aim of this communication to deeply treath TCI device or the way of using it, but it was compulsory to me to define in a short way the TCI concepts, because in my opinion, this is an absolute way to look after anesthesia (when we talk of intravenous anesthesia). Not more." which exact quantity of drug do I have to administer to a patient to get the desired effects?" but "……if I want to have a specific, targeted, controlled effect when I administer an anesthetic drug with a bolus followed by a continuous effect, which are the changes that this drug undergoes until it chains the receptors and which is the distribution volume of the drug that has to be mantained from the device to avoid the so called No Valley anesthesia, Intraoperative Awakening, drug overload? " In order to do this, the TCI considers In real time: A. Distribution volume of the drug B.
Metabolism of the drug C. Clearance of the drug

D. Receptor interaction at bio-phase (even if bio-phase is not anatomically defined)
The TCI t-Peak Time considers the time in which the drug reaches the desired Target concentration. My simple consideration is that in the beginning, when I was in Glasgow with Gavin Kenny, who is the inventor of TCI, it was very difficult for anesthesiologists to accept this new point of considering drugs as they were using them.
A retraining of the drug effects was needed because it was compulsory to learn the different actions of drugs at different distribution volumes! In the case of volatile agents, a similar option can now be considered; as I said before, the Automatic gas Control (F-i-AGC) gives us the opportunity to decode and target before starting the volatile agent to the patient the time that the gas has to be administered to reach the desired effect.
Since 2004 there was not a pediatric dedicated TCI system. The first application has been experimentally done from the author in Glasgow in 1996. TCI was delivered for the use in adults or in patients weighting >30kg. In 2004 Absalom, Lal, Kenny registered a system called "Pdfusor2 for the use in patients weighting <30 kg.
The Pd-Pk parameters of the software were studied from others authors ,as Kataria and Minto, for the use of Ketamune or alfentanyl, but it is singular that in the last 15 years the Pediatric use of TCI has not been well studied and we still do not have dedicated devices to give computer -driven anesthesia to neonates and toddlers. My opinion is that, nowadays ,we are in the same situation of the late 1980s. The peculiarity of anatomy, physiology, pathology diagnosis, weight, eight and organ immaturity or transitory dysfunctions are the basis to propose a different approach to anesthetic procedures.
The research in the field of premature receptor for pain, depression of central nervous system and consequences of anesthesia on the noble organ, requires a precise and specific approach, especially in the pharmacodinamic-pharmacokinetic field regarding anesthetic drugs pathways to perform anesthesia from premature age to 30kg of weight.
A revolutionary change is required in the pharmacological approach.
This change can come from the past.
We must consider what has been already done and studied to explain the changes happening in the field of a very rapid cell growth biochemistry. The Kleiber laws, consider the therapeutic adaptations to cellular growth: there has been a great interest in the study of the rapid cells development and growth characteristics, especially in the research of cancer cells metabolic functioning; a consideration is necessary as consequence of this observation: only another type of rapid growth exists in biology and is the neonatal and pediatric growth as established from the Tanner-Whitehose Percentile Growth.
Kleiber laws define a non-linear relationship between the SIZE of the patient and the organ function.
At the basis of this relationship is the metabolic power related to the body mass of the patient: Where: P= Pharmacokinetic parameter to be adopted C) The De Castillo-Katz law that defines how many receptors are able to develop an action : Where AR are active complex and AR* are inactive complex.
We have a slope curve defined as "EC slope curve" that gives us in real time the drug concentration at the effect site. Many others allometric laws are required to define a new pd-pk model , and at the moment a dedicated manuscript that describes new pharamacological relationship concepts is on the way to be submitted for publication.

Conclusion
A huge number of covariate values need to be recognized and inserted in a new software to create a new pd-pk pharmacological model to give a correct anesthesia to young patients and old patients; allometric laws must be strictly related one to the other in order to obrain this dedicated pd-pk model.
A new anesthetic approach is compulsory; the evidence of the great differences that are at the basis of neonate and toddlers anatomic and functional developmental pathways, needs to to be undertaken from the new pd-pk concepts; new theoretic distribution volume has to be defined and mathematically fixed to perform computer-driven anesthesia in this kind of patients, but in my personal opinion the pharmacological concepts we are rarely used to work with are not enough precise and adequate to get this result.
The conceptual equation regulating a thricompartimental theoretical deep equilibrium at bio-phase model is correct by itself, but in neonates, toddlers and elderly patients a quantistic biomolecular pd-pk pharmacological approach is compulsory. A change in anesthetic approach must give to anesthetists the chance not only to recognize a correct anesthesia delivery from the analysis of the clinical drug effect reported data, but give them the skills and the devices to deliver a personal and dedicated anesthesia for each patient requirements starting from a predefined targeted point break.