Physiology for obese elderly and peds.pdf

5 Physiology and Pharmacology of Obesity, Pediatrics, and the Elderly KEN B. JOHNSON, TRAVIS BAILEY, AND ELIZABETH THACKERAY CHAPTER OUTLINE Obese Patients Obese Patients Physiologic Changes in Obese Patients Anesthetic Pharmacology in Obesity Sedative-Hypnotics Opioids Inhaled Anesthetics Neuromusc...

5 Physiology and Pharmacology of Obesity, Pediatrics, and the Elderly KEN B. JOHNSON, TRAVIS BAILEY, AND ELIZABETH THACKERAY CHAPTER OUTLINE Obese Patients Obese Patients Physiologic Changes in Obese Patients Anesthetic Pharmacology in Obesity Sedative-Hypnotics Opioids Inhaled Anesthetics Neuromuscular Blocking Drugs Local Anesthetics Physiologic Changes in Obese Patients Pediatric Patients Physiologic Changes in Pediatric Patients Anesthetic Pharmacology in Pediatric Patients Inhaled Anesthetics Propofol Midazolam Etomidate Ketamine Opioids Neuromuscular Blocking Drugs Anesthetic Toxicity in Neonates and Infants Elderly Patients Physiologic Changes in the Elderly Anesthetic Pharmacology in the Elderly Postoperative Cognitive Dysfunction Emerging Developments Open Target-Controlled Infusion A nesthesiologists frequently care for patients at the extremes of age and size. These patient groups have unique features that require special consideration when formulating an anesthetic plan. The purpose of this chapter is to highlight alterations in physiology associated with these special populations, focusing in particular on how the altered physiology influences the behavior of anesthetic drugs as covered in other chapters. To translate this information into the clinical domain, the chapter aims to summarize dosing adjustments that account for body habitus (obese and morbidly obese) and age at both extremes (neonates and elderly). Obesity presents anesthesiologists with numerous challenges that affect their care throughout the perioperative period. Excess body weight affects virtually every system of the body, including the cardiovascular, respiratory, endocrine, digestive, and hematologic systems, among others. In particular, increased chest wall mass, redundant airway tissue, and increased incidence of obstructive sleep apnea make this patient group at increased risk for adverse airway and respiratory events among many other weight-related issues (Table 5.1, Fig. 5.1). In response to the increasing frequency of obese patients presenting for surgery, the American Society of Anesthesiologists (ASA) updated the ASA’s Physical Status Classification System to include obesity as a metric to consider when determining a patient’s physical status (Table 5.2).1 This modification encourages clinicians to acknowledge how obesity-related conditions can lead to adverse events in the perioperative period. Of particular relevance to anesthesiology, obesity can alter the pharmacokinetics and effects of intravenous agents (opioids, sedatives, neuromuscular blockers) and inhalation agents. Increased fat mass, increased blood volume and cardiac output, and reduced tissue perfusion change drug disposition that can lead to changes in the magnitude and time course of drug effect2,3 (Table 5.3, see Fig. 5.1). The fact that most anesthetics are highly lipophilic (i.e., as measured by their octanol-water coefficient) raises concerns about accumulation of anesthetics into fatty tissue over the course of an anesthetic. When exploring differences between drugs, however, lipophilicity alone does not reliably predict volume of distribution. Lipophilic drugs can have increased, unchanged, or reduced distribution volumes4 because drug distribution also depends on other properties, such as protein binding, molecular size, ionization at physiologic pH (pKa), among other factors. Understanding the relationship between total body weight, lean body weight, and fat weight is also important. As total body weight increases beyond ideal body weight (i.e., as body mass index [BMI] increases), the proportion of lean and fatty tissue begins to diverge (Fig. 5.2). Above a BMI of 30 kg/m2, lean body weight begins to plateau, and the curve flattens even further as BMI exceeds 40 kg/ m2 as the body has proportionally less lean tissue. Obesity influences the physiology of most organ systems that can alter the pharmacologic behavior of anesthetic drugs. Although drugs from the same class (e.g., opioids) are likely to be influenced by obesity in 91 Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on May 13, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 5 Physiology and Pharmacology of Obesity, Pediatrics, and the Elderly Abstract Keywords Anesthesiologists are frequently asked to care for patients at the extremes of age and size. These patient groups have unique features that require special consideration when formulating an anesthetic plan. The purpose of this chapter is to highlight alterations in physiology associated with these special populations, focusing in particular on how the altered physiology influences the behavior of anesthetic drugs. To translate this information into the clinical domain, the chapter aims to summarize dosing adjustments that account for body habitus (obese and morbidly obese) and age at both extremes (neonates and elderly). obesity pharmacokinetics elderly neonate age size Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on May 13, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 91.e1 92 SE C T I O N I Basic Principles of Pharmacology TABLE Anesthetic Considerations and Perioperative Challenges in Obese Patients 5.1 Weight-Related Condition Challenge Management Considerations Redundant upper airway tissue Obstructive sleep apnea Continuous positive airway pressure to stent open the airway when appropriate (procedures requiring sedation, recovery from general anesthesia) Immediate availability of airway adjuncts (e.g., video laryngoscope, supraglottic airways, elastomeric bougie, fiberoptic bronchoscope) and patient positioning Potential difficulty with airway management (more likely in males107) Redundant tissue over chest and abdomen Reduced functional residual capacity108 With mechanical ventilation, may require high airway pressures to achieve adequate ventilation,109 leading to an increased risk of barotrauma Induction of anesthesia: Anticipate rapid drop in oxygen hemoglobin saturation once rendered apneic despite effective preoxygenation Emergence from anesthesia: Extubate to continuous positive airway pressure. Place head of bed to 45° to optimize pulmonary mechanics. Maintain plateau airway pressures 40 kg/m2) comparing a dose of 1 mg/kg using three different weight scalars: IBW, LBW, and TBW. Across groups, there was no difference in onset time. Longer recovery time correlated with the larger overall dose (e.g., 1 mg/kg using TBW being the largest), 97 although recovery times were relatively short compared with other longer-acting neuromuscular blocking drugs. Intubating conditions were adequate in all groups, but laryngoscopic view was better in the group dosed to TBW. The authors recommended dosing succinylcholine based on TBW,38 prioritizing the laryngoscopic view over duration of blockade. Studies comparing TBW and IBW as the basis for dosage calculation for rocuronium in morbidly obese patients found that at a dose of 0.6 mg/kg using TBW led to a prolonged duration of action but did not improve intubating conditions compared to IBW.39,40 Similar results have been observed with vecuronium.41-43 Thus the consensus is to dose rocuronium and vecuronium to IBW to achieve a shorter duration of blockade without compromising intubating conditions. For neuromuscular blockade reversal with sugammadex, weight scalar recommendations vary. Some authors recommend using IBW and others suggest using ABW,44,45 whereas a pooled analysis of 1418 adult obese patients led to a recommendation that sugammadex be dosed according to TBW.46 Given the favorable sugammadex safety profile, dosing to TBW is a reasonable approach. Reversal doses are a function of blockade depth. Use of a peripheral nerve stimulator capable of quantitative train-of-four monitoring allows accurate determination of blockade depth and the appropriate sugammadex dose. In brief, profound (no train-of-four, no posttetanic twitch), deep (no train-of-four, one or more posttetanic twitches), moderate (one to three train-of-four count), shallow (train-of-four ratio 0.1-0.4), and minimal (train-of-four ratio > 0.4) blockade are reversed with 16, 4 to 8, 2, 2, and 2 mg/kg of sugammadex, respectively. An interesting feature of sugammadex reversal is that it can be used to provide rapid reversal after administration of high-dose rocuronium (e.g., 1.2 mg/kg) following a rapid sequence induction. In an emergency setting of “can’t intubate and can’t oxygenate,” deep blockade by rocuronium can be completely reversed faster than spontaneous recovery from an intubating dose of succinylcholine (1 mg/kg).47 Although sugammadex reversal is fast regardless of blockade depth, a simulation study concluded that residual effects from induction doses of sedatives and opioids may persist after blockade reversal.47 Thus, although they are no longer paralyzed, patients can remain unresponsive or have significant respiratory depression. If both unresponsiveness and respiratory depression exist, patients might not be able to self-rescue from a “can’t intubate–can’t oxygenate” scenario. Given that obese patients have reduced functional residual capacity and a shortened time to oxygen-hemoglobin desaturation when rendered apneic despite adequate preoxygenation, they are at increased risk for hypoxia.47 Another important consideration when administering a large sugammadex dose (e.g., 16 mg/kg) is that the dose might not be immediately available at the point of care without proper preoperative planning and preparation. Local Anesthetics The safe dose of local anesthetics varies with the route of administration, the properties of the local anesthetic, and the addition of epinephrine. Plasma concentrations are the highest after intercostal nerve block and decrease as follows: intercostal > caudal > epidural > brachial plexus > sciatic/femoral.48 Plasma concentrations of local anesthetics do not correlate well with body weight or BMI in adults but correlate better with weight in children.49-51 Local anesthetic toxic doses have not been well studied in obese patients. The widely recommended axiom of the smallest effective dose is appropriate in this patient population. Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on May 13, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 98 SE C T I O N I Basic Principles of Pharmacology Pediatric Patients Anesthetic Pharmacology in Pediatric Patients When formulating an anesthetic dosing regimen for a pediatric patient, an important consideration is that children are not miniature adults. Anatomic and physiologic changes that occur between the newborn period and adult life have important pharmacologic implications. In part because the early drug development process is focused on adult volunteers and patients, these developmental changes are often not well accounted for in available dosing guidelines. Ideally, dosing recommendations should be based on research in children along all phases of development and maturation to characterize drug pharmacokinetics and pharmacodynamics properly. Unfortunately, detailed information along these lines is not available for most anesthetics. Given the cost of drug development, pharmaceutical companies often seek approval from regulatory agencies for adults, but not children. As such, many anesthetics are administered “off-label” using adult doses scaled to pediatric patients. In response, the United States National Institute of Childhood Health and Human Development formed the Pediatric Pharmacology Research Unit Network in 1994, and in 1997, the U.S. Food and Drug Administration (FDA) developed the Modernization Act52 to incentivize drug research in pediatric patients by extending the duration of market exclusivity for approved drugs. One challenge is to account for changes in body composition, metabolic capacity, and body surface area that occur with age. Several approaches have been explored (e.g., dosing based on body surface area or allometric scaling), but the most common approach is to use weight-normalized dosing according to age (e.g., where available milligrams per kilograms for neonates up to 44 weeks’ postconception in age), infants (1-12 months of age), and children (up to 12 years of age). In general, anesthesiologists can expect significant variability in anesthetic dosing of pediatric patients.53 Thus only general dosing guidelines are possible for most anesthetic drug classes. A brief discussion of dosing recommendations for selected anesthetics is provided in the following text and summarized in Table 5.8. Physiologic Changes in Pediatric Patients Neonates, infants, and children present anesthesiologists with challenges throughout the perioperative period. Selected physiologic changes such as differences in airway anatomy, chest wall and respiratory system function, and cardiovascular function place this patient group at increased risk for adverse airway and respiratory events as well as other pediatric issues (Table 5.7, Fig. 5.7). For many of these physiologic changes, inherent variability is associated with maturation and interpatient and intrapatient differences that influence anesthetic drug behavior and alter dosing considerations. For example, neonates and infants have greater total body water than their adult counterparts, resulting in a larger volume of distribution with water-soluble drugs such as succinylcholine and many antibiotics. With a larger volume of distribution, a higher initial loading dose is required to achieve therapeutic plasma concentrations. Neonates also have lower serum albumin and total protein concentrations, resulting in higher free plasma levels of highly protein-bound drugs, such as bupivacaine, opioids, sedatives, and antibiotics. The kidneys and liver of neonates are immature compared with those of adults. The developmental physiology of the liver is complex, but in general hepatic enzymatic drug metabolism is decreased in neonates, and the neonatal liver receives disproportionately less cardiac output than an older child or adult. The neonatal kidney is less efficient, prolonging the half-life of drugs primarily excreted through the kidneys. Neonates also have a decreased proportion of body mass as fat and muscle, which can prolong drug effects depending on redistribution into those tissues. Inhaled Anesthetics Potent inhaled agents are frequently used in pediatric anesthesiology because of their utility for mask induction. The minimum alveolar concentration (MAC) varies with age (see Table 5.8): neonates have a MAC 20% less than that of infants,54 and premature infants have an even lower MAC.55 MAC increases through infancy until age 3 to 5 and then declines steadily with age.56,57 In general, the MAC of an infant is 1.6 to 1.8 times the MAC of a 40-year-old adult, and the MAC of a premature infant is 1.2 to 1.6 times lower than that of an infant. With significant interpatient variability, anesthesiologists titrate the dose of inhaled agents and administer intravenous adjuncts (e.g., opioids, nonsteroidal antiinflammatory drugs) to meet anesthetic requirements (e.g., minimize patient movement, maintain blood pressure, blunt or block the response to a painful stimuli). Propofol Comparison to other anesthetics, propofol has been well characterized in neonates and children. Prior work has established that dosing by TBW is best and that children can require up to 50% to 100% more propofol than in adults.58 For example, neonates required a 3-mg/kg bolus to tolerate chest tube removal. Of note, propofol is metabolized more slowly in neonates compared with children until about 3 months of postnatal life or 54 weeks’ postgestational age.59 A serious concern with propofol when administered to pediatric patients for sedation during mechanical ventilation is propofol infusion syndrome. Development of the syndrome is more likely when propofol is administered at rates above 67 µg/kg per minute (4 mg/kg per hour) for more than 48 hours. Presenting signs include hyperlipidemia, rhabdomyolysis, refractory bradycardia leading to asystole, and/or lactic acidosis.60 The syndrome is often lethal; treatment consists of discontinuing propofol and supportive care. Early diagnosis of propofol infusion syndrome is key to achieving a good outcome. The mechanism of propofol infusion syndrome is unclear, but one hypothesis is that propofol disrupts mitochondrial fatty acid metabolism to cause an accumulation of fatty acids that can induce life-threatening ventricular arrhythmias.61 Another hypothesis suggests that propofol impairs mitochondrial function, disrupting electron transport and oxidative phosphorylation, causing metabolic acidosis and cellular hypoxia.62 Midazolam Midazolam is a useful adjunct and premedication to minimize separation anxiety and fear and can be administered by multiple routes (intranasal, intravenous, rectal, oral, intramuscular, or sublingual, see Table 5.8). When administered as an intravenous bolus, its anxiolytic effect begins within 1 to 2 minutes, giving the impression that it is a fast-acting drug. Although it has a rapid onset of anxiolytic effect, it requires 6 to 9 minutes to reach peak effect and has a long decrement time. When administered by mouth, midazolam has a slower onset of effect (20-30 minutes). Suggested oral doses of 0.5 to 0.75 mg/kg should be administered Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on May 13, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 5 Physiology and Pharmacology of Obesity, Pediatrics, and the Elderly 99 TABLE Anesthetic Considerations and Perioperative Challenges in Neonates and Infants138 5.7 Neonate-/Infant-Related Condition Challenge Management Considerations Airway anatomy Large head with prominent occiput Large tongue Preferential nose breather—breathing difficult with excessive secretions Glottic opening at level of C3-C4 Long epiglottis—can flop posteriorly Narrowest segment of the airway is subglottic Airway obstruction Position head and neck to maintain in a neutral position Where feasible, maintain patent nasal passages Consider small endotracheal tube to minimize postextubation stridor Position endotracheal tube to avoid inadvertent extubation or endobronchial intubation with head movement (target 1 cm above the carina) Chest wall anatomy and pulmonary physiology Compliant chest wall Ventilation is primarily from the diaphragm Ventilation is rate dependent Closing volume is larger than the functional residual capacity (until age 6 years) Work of breathing may exceed 15% of oxygen delivery Thick-walled alveoli Fewer alveoli (10% of adult) Frequent postoperative apneas in premature infants Limited respiratory reserve Reduced functional residual capacity that is further reduced with apnea and anesthesia Apneas longer than 15 seconds or associated with hypoxia and bradycardia Induction of anesthesia: Anticipate rapid drop in oxygen hemoglobin saturation once rendered apneic despite effective preoxygenation Consider decompressing stomach if abdominal pressure is limiting diaphragm movement. Caution with aggressive bag mask ventilation Consider using positive end-expiration pressure, continuous positive airway pressure, or intermittent positive-pressure ventilation to stent open airway and reduce work of breathing Vigilant postoperative respiratory monitoring in high-risk neonates and infants Consider caffeine 10-20 mg/kg oral or intravenously Cardiovascular system Fixed stroke volume Cardiac output is heart rate dependent High vagal tone Prone to bradycardia and low cardiac output Treat neonates with heart rate 3 yr) IV: Sedation (infusion) PO: Premedication Intranasal: Premedication IV: Premedication Intranasal: Sedation IM: Sedation IV: Sedation (age 6 mo to 5 yr) PR: Sedation SL: Sedation IV infusion: Sedation (neonates 32 wk) IV: Induction IV: Sedation PO: Premedication IM: Premedication IV: Sedation IV: Induction IV: Analgesic IV: Analgesic (infusion) 2.5-3.5 mg/kg 125-150 µg/kg/min 0.25-0.5 mg/kg (maximum 20 mg) 0.2-0.3 mg/kg 0.05 mg/kg 0.2-0.3 mg/kg (maximum 10 mg per dose) 0.1-0.15 mg/kg 0.05-0.1 mg/kg (maximum 6 mg) 1 mg/kg 0.5-0.75 mg/kg 0.03 mg/kg per hour 0.06-0.12 mg/kg per hour; titrate to effect 0.3 mg/kg (0.2-0.6 mg/kg) 0.1-0.3 mg/kg; repeat as needed 6-10 mg/kg 3-7 mg/kg 0.5-2 mg/kg per dose 1-2 mg/kg 0.1 mg/kg 0.1-0.3 mg/kg per hour Sedatives Propofol139,140 Midazolam140-143 Etomidate65,140,144,145 Ketamine140,146-148 Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on May 13, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. CHAPTER 5 Physiology and Pharmacology of Obesity, Pediatrics, and the Elderly 101 TABLE Dosing Considerations of Selected Anesthetics in Pediatric Patients—cont’d 5.8 Drug Route of Administration Dose IV bolus: Analgesic IV bolus: Loading dose IV: Infusion Intranasal Oral transmucosal fentanyl IV: Bolus IV: Infusion IV bolus: Loading dose IV: Infusion Intranasal PO (children) PO: (adolescents) IV: Bolus IV: Continuous Caudal PO: Immediate release PO: Continuous release IV: Infusion (neonates) IV: Infusion (children) Caudal Intrathecal 1-2 µg/kg 5-10 µg/kg 1-3 µg/kg per hour 1-2 µg/kg 5-15 µg/kg 1 µg/kg 0.25-3.0 µg/kg per minute 1-2 µg/kg 0.1-0.2 µg/kg per hour 2 µg/kg 0.05 mg/kg q4-6h 1-4 mg-dose q4-6h 5-10 µg/kg q4-6h 3-5 µg/kg per hour 10 µg/kg 0.3 mg/kg per dose q4-6h 0.3-0.6 mg/kg per dose q12h 0.01-0.02 mg/kg per hour 0.01-0.04 mg/kg per hour 30-50 µg/kg 5-7.5 µg/kg Opioids Fentanyl149-151 Remifentanil149,152,153 Sufentanil154-156 Hydromorphone149,157 Morphine158-160 Neuromuscular Blocking Agents and Reversal Succinylcholine161-163 Rocuronium164,165 Vecuronium166,167 Cisatracurium168,169 Sugammadex170,171 IV: Fast onset IM IV: Intubation IV: Maintenance IV: Intubation IV: Maintenance IV: Intubation IV: Maintenance IV (train of four 1-2/4) IV (profound paralysis) 1.5-2 mg/kg 4 mg/kg 0.3-1.0 mg/kg 0.1 mg/kg 0.05-0.1 mg/kg 0.02 mg/kg 0.1-0.2 0.02-0.05 2-4 mg/kg 16 mg/kg Inhaled Anesthetics Drug Indication MAC Isoflurane Preterm (