7.1 History of General Anesthesia

Attempts at producing a state of general anesthesia can be traced throughout history in the writings of the ancient Sumerians, Babylonians, Assyrians, Egyptians, Greeks, Romans, Indians, and Chinese. The Renaissance made significant advances in anatomy and surgical techniques, despite all this progress only with the discovery and introduction of general anesthesia in late eighteenth century permitted development of modern surgery.

Humphry Davy (1778–1829) discovered the anesthetic properties of nitrous oxide, call it laughing gas and published his findings in the systematic written scientific work. He was the first to document the analgesic effects of nitrous oxide, as well as its benefits in relieving pain during surgery. Horace Wells (1815–1848) was an American dentist who pioneered the use of anesthesia in dentistry, specifically he studied nitrous oxide during painless tooth extraction (Fig. 7.1). Subsequently, his apprentices William Morton (1819–1868) in Boston made first public demonstration on the use of ethereal general anesthesia for surgical operation on the neck without pain. He used a glass sphere (Fig. 7.2) containing a sponge soaked in ether which evaporated and brought the patient to sleep. Friedrich Wilhelm Adam Sertürner (1783–1841) was a German pharmacist and a pioneer of alkaloid chemistry. Sertürner in 1805 isolated successfully morphine extract crystals from the opium poppy (Papaver somniferum) (Fig. 7.3). After a series of experiments on rats and stray dogs, he reported his discovery of a sleep-inducing molecule. Since his discovery occurred almost 50 years before the invention of the hypodermic syringe, the drug had to be administered orally. He was a pioneer and promoted a new branch of science that came to be known as alkaloid chemistry. John Snow (1813–1858) conducted translational research that permitted him to understand the mechanisms of vaporizing volatile anesthetic agents, ether and chloroform, so that safe delivery systems of anesthesia could be designed. He made about 4000 anesthesia and treated 77 obstetric patients with chloroform using chloroform as an anesthetic for childbirth and brought obstetric anesthesia to be accepted against religious, ethical, and medical beliefs by administering chloroform to Queen Victoria for the births of Prince Leopold and Princess Beatrice (Figs. 7.4 and 7.5) [1]. Robert Macintosh (1897–1989) designed laryngoscope, endobronchial tube, and anesthetic vaporizer. He travelled widely, giving demonstrations of safe and simple anesthesia.

7.2 Introduction

The history of in vitro fertilization (IVF) and embryo transfer (ET) dates back as early as the 1890s when Walter Heape, a professor at the Cambridge University, United Kingdom, reported the first known case of embryo transplantation in rabbits. In vitro fertilization and ET technology developed rapidly in humans since the first successful birth of a child (Louise Brown) occurred in 1978 as a result of a scientist Robert Edwards and his gynecologist Patrick Steptoe’s IVF techniques [2] (Fig. 7.6).

The assisted reproductive technologies have evolved tremendously since the emergence of IVF techniques and today anesthesiologists play an important role in the process of oocyte retrieval and other IVF-related procedures [3]. A variety of anesthetic techniques like conscious sedation, general anesthesia, and regional anesthesia have been tried with none being superior to the other. However; irrespective of the techniques the key point of anesthesia for IVF is to provide the anesthetic exposure for least duration so as to avoid its detrimental effects on the embryo cleavage and fertilization.

In vitro fertilization treatment is most commonly conducted using exogenous FSH to induce follicular growth and human chorionic gonadotropin (hCG) to induce final oocyte maturation. It is very important for the gynecologists that the harvesting of oocytes takes place within a defined period of time to ensure the best fertility outcomes. These oocytes are subsequently fertilized in vitro and allowed to develop into embryos that are finally transferred into the uteri of patients.

In the beginning, oocyte harvesting was performed by laparoscopy, a process that required the administration of general anesthesia in the hospital setting. The technological progress and development of transvaginal ultrasounds allowed oocyte retrieval from the ovary through the puncture of the vaginal wall under the ultrasound guide and under conscius sedation (Fig. 7.7).

Oocyte (egg) retrieval for in vitro fertilization is a relatively short procedure, usually performed as an outpatient. The duration of oocyte retrieval is on average several minutes (maximum a half an hour), depending on the amount of follicles to be aspirated and the anatomical position of the ovaries. It is a common belief that when the duration of oocyte retrieval procedure is >10–15 min, immediate post-procedure pain score is significantly higher compared to those patients whose procedure where for <10–15 min.

Conscious sedation is the most commonly used technique in IVF because it is relatively safe. Target-controlled infusion (e.g., propofol) is a suitable anesthetic technique. Propofol is the preferred anesthetic agent for oocyte retrieval, but should be used by specially trained personnel (Figs. 7.8, 7.9, and 7.10). After the oocyte retrieval, women are kept under observation for a few hours to make sure that there are no complications and they have regained the level of consciousness. Usually, the discharge from the IVF center takes place for a few hours (e.g., 2–4 h) after the oocyte retrieval.

Furthermore, an increased attention has also developed the potential adverse effects of different types of anesthesia, not only on the patients undergoing oocyte retrieval but also on the quality of the oocytes that may eventually effect embryo development and pregnancy success [4, 5].

7.3 Oocyte Retrieval: Pre-procedure Considerations

Oocyte retrieval for in vitro fertilization is one of the most common minor surgical procedures. As in any surgical procedure, there are some common basic requirements that should be fulfilled before any technique can be used in the treatment of patients. The anesthetic agent should be easy to administer, its effects should be easily monitored, and short-acting agents with ready reversible effects should be used. Adequate pain control is of paramount importance. A multidisciplinary approach is necessary to obtain a better diagnostic classification of women who present themselves for assisted conception, and subsequently better reproductive technologies outcomes. Obstetric anesthesia is considered a high-risk subspecialty of anesthesia [6, 7]. A long series of evidence-based guidelines and reviews of mortality and morbidity have been used to adopt constant improvement in maternal safety and perioperative outcomes [8–11].

Usually, this population of patients is healthy and in their 30–40 years, however some women might present with various comorbidities (e.g., hypertension, diabetes mellitus, obesity) [3]. The development of the transvaginal approach for oocyte retrieval has allowed the possibility of using sedation for most cases and regional anesthesia and/or general anesthesia only with more complex cases where sedation might not be adequate.

The American Society of Anesthesiologists classification of physical status (ASA PS) is a widely used system for categorizing the preoperative status of patients [12]. The ASA class is a good independent predictor of perioperative morbidity and mortality. However; the definitions of the ASA classes have been amended several times since 1941, resulting in inconsistent and confusing usage in the current literature.

Since most of the anesthetic agents, either inhalational and/or intravenous, reach the follicular fluid within minutes after administration [13], they should be devoid of any toxic effects on the oocyte.

Guasch et al. [14] designed a clinical trial to determine the plasma and follicular levels of prolactin and cortisol in patients in an assisted reproduction program. Women were randomized to three anesthetic groups: (1) general anesthesia, (2) spinal anesthesia, or (3) sedation with alfentanil and midazolam plus paracervical block. Patients were consecutively assigned to the fourth group (4) to receive sedation with remifentanil plus paracervical block. The patients receiving general anesthesia had the greatest increase in prolactin by the end of the procedure. Follicular cortisol increased in the paracervical block group in which remifentanil was used for sedation. The only significant difference between groups was seen for the rate of gestation of 0% in the group receiving sedation with alfentanil and midazolam before a paracervical block. Adverse effects were few with all the techniques [14]. The authors concluded that plasma increases in prolactin and hormonal responses to follicular puncture were fully attenuated by spinal anesthesia and partially attenuated by the techniques requiring sedation. None of the anesthetic techniques proved harmful to oocytes or embryos. Nor was the effectiveness of the in vitro fertilization technique affected by any of the anesthetic techniques studied [14].

Gejervall et al. [5] in a retrospective observational study compared the effect of different doses of alfentanil (Fig. 7.11) on two primary endpoints, fertilization rate and good quality embryo (GQE) rate 663 (N = 663) women. The authors concluded that the amount of alfentanil is not associated with adverse effects on fertilization rate, embryo development, or clinical pregnancy rate, which is reassuring and indicates that women can be offered adequate pain relief [5].

A total of 202 patients undergoing fertility treatment was included in a prospective, matched, controlled study, in which Christiaens et al. [15] compared fertilization rates and embryo development in terms of morphological quality and speed of development and the implications for reproductive outcome and pregnancy following general anesthesia using either propofol or a paracervical local anesthetic block during oocyte collection. The authors concluded that there were no differences between the fertilization rates and the embryo cleavage characteristics for the two groups. The initial implantation rate per transferred embryo after general anesthesia was similar to that after paracervical local anesthetic block (13.4 versus 18.6%; P = 0.10). The ongoing clinical implantation rates per embryo transfer were also similar in the two groups [15].

Janssenswillen et al. [16] designed a study to assess the effect of propofol on fertilization and early embryo development in a mouse IVF model. Where fertilization occurred, subsequent embryo cleavage and development up to the blastocyst stage was affected significantly by the presence of propofol solution in the medium, (i.e., 3–41%) in comparison with the control group (76%). Exposure of unfertilized oocytes for 30 min to propofol results in a parthenogenetic activation of 33–60%, which was significantly higher than the control (10%). When oocytes were kept in propofol for 24 h, a mean of 30% of activation was observed as compared with 0.5% for the control. The authors concluded from these experiments that even a brief exposure of cumulus-enclosed oocytes to a low concentration of propofol is deleterious to subsequent cleavage. Exposure of unfertilized oocytes to propofol results in a high degree of parthenogenetic activation [16].

Hammadeh et al. [17] conducted a study to compare the effects of two different anesthetic techniques (general anesthesia versus sedation) used for oocyte retrieval on IVF outcome. For general anesthesia, the authors used a combination of remifentanil (Ultiva) with either propofol or isoflurane in hypnotic concentrations. For sedation, the protocol included midazolam, diazepam, or propofol according to clinical needs. In total, 202 women were enrolled in the study. Ninety-six women opted for sedation and 106 for general anesthesia. The number of collected oocytes was significantly higher with general anesthesia (10.54 ± 5.43 [mean ± SD]) than with sedation (6.25 ± 3.65, P < 0.0001), whereas the number of fertilized oocytes was not different (4.70 ± 3.57 vs. 4.23 ± 2.90). There were no significant differences in cleavage and pregnancy rates. The authors concluded that remifentanil-based general anesthesia without nitrous oxide is a suitable alternative to sedation and may be recommended for IVF oocyte retrieval if general anesthesia is requested [17].

Sterzik et al. [18] studied the effect of different anesthetic procedures on hormone levels in women. Fifty-four patients awaiting transvaginal oocyte aspiration were randomized into three groups: (1) anesthesia with ketamine as an induction agent and analgesic (n = 20); (2) general intubation anesthesia using thiopentone for induction and enflurane for maintenance (n = 18); and (3) no anesthesia (n = 16). Estradiol, progesterone, prolactin, and beta-endorphin were measured from day 3 to 14 referring to follicle aspiration. Differences between preoperative hormone levels and their intra- and postoperative peaks were analyzed using the Kruskal-Wallis test (P < 0.03). The authors concluded that the increased prolactin and beta-endorphin plasma levels associated with ketamine and general anesthesia reflect a significant alteration of the observed hormone levels. When anesthesia is indicated, they try to avoid general intubation anesthesia in favor of ketamine [18].

7.4 Principles of Anesthesia for Oocyte Retrieval

7.4.1 Preanesthetic Evaluation

The preanesthetic evaluation of patients scheduled for oocyte retrieval is similar to that of other preoperative patients, with a focus on assessment of the airway (Figs. 7.12, 7.13, and 7.14), lower back (Fig. 7.15), and coexisting patient’s medical conditions. Challenges and complications related to anesthesia are more common in obese patients (see Figs. 7.12, 7.13, and 7.14) and include difficulty with monitoring, positioning, airway management (Figs. 7.16, 7.17, 7.18, 7.19, 7.20, 7.21, and 7.22), and neuraxial techniques (Figs. 7.23, 7.24, and 7.25) [19]. In patients with specific medical issues, such as predicted difficult airway (see Figs. 7.12, 7.13, and 7.14) or (rarely) malignant hyperthermia susceptibility, there are additional reasons to avoid general anesthesia. Therefore, anesthesiology consultation is always recommended.

IVF procedures can be conducted with local infiltration, neuraxial anesthesia, and conscious sedation and under general anesthesia.

7.5 Sedation

The American Society of Anesthesiologists (ASA) House of Delegates approved the definition of General Anesthesia, Depth of Sedation, Levels of Sedation/Analgesia [20]. Minimal Sedation (Anxiolysis) is drug-induced state during which patients respond normally to verbal commands. Citations from the ASA document are listed below:

Their definition:

Minimal Sedation (Anxiolysis) is a drug-induced state during which patients respond normally to verbal commands. Although cognitive function and physical coordination may be impaired, airway reflexes, and ventilatory and cardiovascular functions are unaffected.

Moderate Sedation/Analgesia (Conscious Sedation) is a drug-induced depression of consciousness during which patients respond purposefully^{1 , 2} to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained.

Deep Sedation/Analgesia is a drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully² following repeated or painful stimulation. The ability to independently maintain ventilatory function may be impaired. Patients may require assistance in maintaining a patent airway, and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

Conscious sedation, defined as a “minimally depressed level of consciousness that retains the ability of the patient to maintain a patent airway independently and continuously and to respond appropriately to verbal commands” [21], is currently the most common form of anesthesia used during oocyte retrieval in the United States [22]. Conscious sedation can be achieved either with inhalation or intravenous agents. Intravenous agents are more popular because they cause less postoperative nausea and vomiting and are easier to administer.

7.5.1 Agents Used for Conscious Sedation

Opioids (morphine, meperidine, fentanyl, alfentanil) (see Figs. 7.3, 7.11, and 7.26) are used in conscious sedation primarily for their analgesic effects. Opioids act on the hypothalamus to decrease the body’s response to the stressful stimuli. Opioids have a direct effect on the medulla, producing a dose-dependent depression of respiration in response to hypercapnia. Opioid administration decreases minute ventilation by decreasing respiratory rate and may lead to apnea. Rapid administration of opioids can induce rigidity of the thoracic muscles (stiff chest syndrome), which can also involve the laryngeal and pharyngeal muscles. This is a potential life-threatening complication that may result in the inability to ventilate the patient. Administration of an opioid antagonist such as naloxone or a muscle relaxant such as succinylcholine followed by immediate intubation may be required. Opioids can also cause sedation and have a synergistic effect when given in combination with benzodiazepines. Fortunately, all the effects of opioids, including respiratory depression and pruritus, can be readily reversed with the administration of opioid antagonists, with the exception of the stiff chest syndrome that may require the additional administration of muscle relaxants.

Benzodiazepines (midazolam, diazepam, lorazepam) are used mainly because of their sedative, anxiolytic, and amnesic effects. Their analgesic effect is minimal. Additional properties of benzodiazepines include muscle relaxation through their action on spinal internuncial neurons and anticonvulsive effects. In combination with opioids, their sedative effects are enhanced, therefore allowing the use of reduced doses of both medications. However, the concurrent use of benzodiazepines and opioids may increase the incidence of apnea and respiratory depression. This effect is more prominent in patients with chronic obstructive pulmonary disease. Benzodiazepines offer only antegrade amnesia (patients do not have any recollection of the events following administration) so it is important to ensure that they are given early enough in the procedure.

Propofol, a relatively new agent, has been widely used either alone or in combination with other agents for oocyte retrieval. It provides rapid onset of analgesia and anesthesia, short duration of action, and rapid recovery with minimal drug accumulation. The mechanism of action of propofol is poorly understood. It has been reported that it may inhibit excitatory stimuli in the olfactory cortex and spinal cord through inhibition of the N-methyl-D-aspartate receptor (NMDA) channels. In addition, propofol seems to potentiate gamma-aminobutyric acid (GABA)-mediated synaptic inhibition in a variety of systems [23, 24] (see Figs. 7.8, 7.9, and 7.10). Propofol administration has been associated with a dose-dependent decrease in systemic blood pressure due to a decrease in systemic vascular resistance and suppression of myocardial contractility. These effects, in combination with a dose-dependent respiratory depression that ultimately results in apnea requiring assistance of ventilation, make propofol use appropriate only by personnel skilled in airway management (see Figs. 7.16, 7.17, 7.18, 7.19, 7.20, 7.21, and 7.22).

Most often a combination of propofol, fentanyl, and midazolam is used for conscious sedation. After an intravenous access has been established, the patient is connected to the standard American Society of Anesthesiology (ASA) monitors that record blood pressure every 3–5 min, oxygen saturation, continuous electrocardiogram, heart rate, percentage of inspired oxygen, and end tidal carbon dioxide. A precordial stethoscope to monitor respiratory rate and the quality of breath sounds is highly advisable. Oxygen 2–4 L/min is administered by face mask throughout the procedure. Initially, midazolam is administered at a dose of 1–2.5 mg to induce anxiolysis and amnesia. Propofol boluses of 10–20 mg are given every 1–2 min until the patient has been adequately sedated. Alternatively, a continuous propofol infusion of 80–150 μg/kg/min can be used. An intravenous local anesthetic such as lidocaine at a dose of 1 mg/kg may be used to decrease propofol-related burning at the site of the infusion. Fentanyl 25 μg titrated slowly to a total of 50–100 μg can also be added to the regimen for postoperative analgesia. For better pain control, the analgesic agent (i.e., fentanyl) should be administered prior to any painful stimuli, a method known as preemptive analgesia. At completion of the procedure, discontinuation of the infusion results in the patient awakening within 3–5 min [25].

Conscious sedation as a method of anesthesia gained its popularity for oocyte retrieval in IVF because it is easy to administer in patients who are motivated and cooperative. In addition, it is very safe to administer in relatively healthy individuals. The majority of women who participate in an IVF program are relatively young, healthy, and motivated. For patients with underlying cardiovascular or respiratory conditions, or for very obese patients, conscious sedation may not be appropriate. There is a fine line between conscious sedation with good pain control and general anesthesia with respiratory suppression that requires assisted ventilation or even intubation. Careful monitoring of the patients by an experienced individual such a registered nurse or an anesthesiologist, and with the use of a pulse oximeter and continuous electrocardiographic monitoring is very important to assure patient safety.

Young couples presenting for infertility treatment at medical attention are commonly anxious, so subsequently of sedation has a positive impact on women undergoing oocyte retrieval: reducing stress, panic, and anxiety. Unfavorable and untoward events can be prevented by accurate, preoperative assessment and proper monitoring in the perioperative period as well as during the emergency [26].

The management of any medical urgency should be conducted with assessment of the airway, breathing and circulation, as outlined in the Basic Life Support Guidelines (IRC—2015).

7.5.2 Complications During Sedation

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  Nausea and Vomiting: Nausea and vomiting may be side-effects of opioids administration. Reduced dose of opioid and use anti-emetic agents as metoclopramide or ondansetron are helpful (see Figs. 7.11 and 7.26).

  
  
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  Pulmonary Aspiration: The aspiration of gastric contents into the lungs usually occurs when the patient is unconscious. This complication may lead to pneumonia, pulmonary distress, and death.

  
  
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  Respiratory Depression: Respiratory depression is defined as apnea, hypopnea, and oxyhemoglobin desaturations. It is important to distinguish the opioid or benzodiazepine-related respiratory depression from airway obstruction. Flumazenil or Naloxone is used for reversal of respiratory depression (see Figs. 7.11 and 7.26).

  
  
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  Airway Obstruction: The airway obstruction can result from pathological condition of anatomical structures or the presence of foreign body (e.g., false teeth). Other causes of airway obstruction include exposure to smoke, asthma (e.g., bronchospasm, laryngospasm), anaphylactoid reaction or hyper-reactive airway. The management depends on the cause and severity of the case.

  
  
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  Hypoxia: It is relatively the most common cardiorespiratory complication during sedation. It is a consequence of respiratory depression or airway obstruction.

  
  
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  Hypotension: Cardiovascular effects of propofol, opioid, or benzodiazepine include decreased cardiac output, systemic vascular resistance, and arterial blood pressure. The literature defines hypotension as declined in blood pressure of less than 90 mmHg which is due to a fall in either cardiac output or total peripheral resistance (leading to drop in the patient’s mean arterial pressure). The use of intravascular fluid supplementation or administration of vasopressor might be beneficial (see Figs. 7.8, 7.10, 7.11, and 7.26).

  
  
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  Hypertension: Causes include systemic hypertension, anxiety, pain, and reflex pressure in response from intubation. Proper preoperative assessment of patients with pre-existing condition/s is necessary.

  
  
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  Arrhythmias, Myocardial ischemia/infarction, and Cardiac arrest: The use of ECG during sedation is mandatory. Sinus tachycardia can be related to pain or hypotension. It is rarely that we can observe myocardical ischemia/infarction and cardiac arrest in these populations of patients.

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