7. Anesthesia and Analgesia for Women Undergoing Oocyte Retrieval
KeywordsOocyte retrievalGeneral anesthesiaPropofolFentanylNeuraxial anesthesiaObesity patientDifficult airway managementPain management
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.
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 . 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.
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.
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) . 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 . 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 , they should be devoid of any toxic effects on the oocyte.
Guasch et al.  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 . 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 .
A total of 202 patients undergoing fertility treatment was included in a prospective, matched, controlled study, in which Christiaens et al.  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 .
Janssenswillen et al.  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 .
Hammadeh et al.  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 .
Sterzik et al.  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 .
7.4 Principles of Anesthesia for Oocyte Retrieval
7.4.1 Preanesthetic Evaluation
IVF procedures can be conducted with local infiltration, neuraxial anesthesia, and conscious sedation and under general anesthesia.
The American Society of Anesthesiologists (ASA) House of Delegates approved the definition of General Anesthesia, Depth of Sedation, Levels of Sedation/Analgesia . Minimal Sedation (Anxiolysis) is drug-induced state during which patients respond normally to verbal commands. Citations from the ASA document are listed below:
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 purposefully1 , 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” , is currently the most common form of anesthesia used during oocyte retrieval in the United States . 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
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 .
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 .
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
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).
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.
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).
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.
Hypoxia: It is relatively the most common cardiorespiratory complication during sedation. It is a consequence of respiratory depression or airway obstruction.
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).
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.
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.