Chapter 86

More documents

Recommendations

Info

1444 PART 5 ■ Anesthetic, Surgical, and Interventional Procedures: Considerations TABLE 86-6. Sulfation and Glucuronidation of Acetaminophen (AA) in Human Neonates and Adults (Formation Rate Constants, HR-1) Age Range AA-Sulfate AA-Glucuronide Sulfate/Glucuronide Neonates 0.099 0.025 4 Adults 0.075 0.170 0.4 Adapted from Levy et al. 96 the liver is exposed to a very high blood flow due to the placenta circulation, which causes hepatic accumulation of anesthetic drugs. Addition ally, maternal metabolism is largely responsible for biotransfor mation and elimination of drugs, a pathway no longer available after birth. Elimination of many drugs such as diazepam is con siderably prolonged in the neonate. 63 The different metabolic pathways of the neonate mature at different rates. Conjugation by sulfation and acetylation are relatively mature, whereas glucuroni dation and conjugation with glutathione and glycine are less well developed. Whereas acetaminophen mainly undergoes glucuroni dation in the adult, it mainly undergoes sulfation in the neonate 64 (Table 86–6). A number of drugs display prolonged elimination half-lives in neonates compared to adults when they mainly undergo hepatic biotransformation (e.g., morphine). 65 Other factors responsible for the prolongation of elimination half-lives are the increased volume of distribution and the very limited, thus easily saturated, enzymatic capacity of the neonate. In the latter instance, elimina - tion may become virtually nil with increasing dosage. 66 On the other hand, certain drugs do not undergo prolonged elimination in neonates. The elimination rate of lidocaine does not signifi - cantly differ from that in adults because its clearance depends less on hepatic metabolism than on liver blood flow, which is fairly similar in neonates and adults. 67 The immature hepatic meta - bolism of certain drugs is to some extent ameliorated by a larger fraction of the drug being excreted unchanged. The urinary excretion of unchanged caffeine represents only 1% of the given dose in adults but may be as high as 85% in the neonate. 68 The transition to extrauterine life as outlined above causes significant changes in hepatic function. With the cessation of the placental circulation the neonate’s liver faces a situation of reduced blood flow and oxygenation while becoming solely responsible for drug metabolism. However, parturition in itself might enhance the maturation of hepatic drug metabolism. Increased glucocorti - coid levels might beneficially affect different enzyme systems 69,70 and the drastic decrease in plasma levels of the inhibitory maternal hormones (e.g., pregnenolone and progesterone 71 ) helps, increas - ing the biotransformation capacity of the liver. Glucocorticoid levels increase during late gestation and will influence the matura - tion of different hepatic enzyme systems. The normal increase in glucocorticoid levels during late gestation or treatment with steroids will affect the maturation of both the UDP-GT enzyme system 71 and certain P450-related activities. 72 Recent scientific evidence has suggested that exposure to drugs able to cause liver enzyme induction during the neonatal period could cause longlasting “imprinted” alteration of hepatic metabolism. 73 Short-term phenobarbital administration to neonatal rodents causes longterm enzymatic changes, still recognizable in adult rats compared to control animals. 74 Exposure to different drugs and other subs tances during the early neonatal period might influence the individual’s drug metabolic pattern later on in life. The implica tions of such neonatally induced hepatic changes in drug metabo lism or hepatic enzyme expression is unknown but raises both questions and concerns. Despite the lack of any obvious short term risks or side effects of medication administered in the neonatal period, further long-term follow-up studies are needed to show that this does not lead to unwanted consequences later on in adult life. Immature hepatic drug metabolism and elimination are likely to be responsible for the increased toxicity of a number of different drugs during early infancy. This is evidenced by lower LD 50 values for many drugs in newly born versus adult animals. 75 This is not true, however, for some drugs such as acetaminophen, which undergoes reduced metabolism by the P-450 system with sub - sequent lower levels of the toxic reactive metabolite responsible for the hepatic toxicity; in this instance, neonates tolerate dosages of acetaminophen that would be hepatotoxic in adults. 76 The issue of the P-450 system in newborns is complex. Comparable total levels of the P-450 system are present before midgestation in human fetal liver 77 but the individual proportions of the various P-450 components differ considerably from adults and the maturation process differ between individual P-450 isoenzymes. Plasma protein binding of alkaline drugs, for example, synthetic opioids and local anesthetics, also differ substantially in neonates compared to adults. Higher free, unbound, and Pharmacologicly active fractions of these drugs will, thus be present in the neonate compared to adults. This in turn is due to much lower plasma levels of -1 acid glycoprotein, the protein mainly responsible for binding of such drugs, found in neonates. Alpha-1 acid glycoprotein levels will gradually increase during infancy and adult levels are reached at about 1 year of age. 78 Alpha-1 acid glycoprotein is one of the acute phase proteins and rapidly increasing levels of -1 acid gly - coprotein (0.1 g/L 24 h) will be seen in neonates following major activation of acute phase system (e.g., major surgery, sepsis or extracorporeal membrane oxygenation). The main issues of im - mature hepatic drug metabolism in the neonate is highly complex but have important clinical implications which are summarized in Table 86–7. Renal Function Formation of new nephrons are completed about 34 to 35 weeks of gestation and further renal growth during late gestation, infancy, and adulthood is caused by enlargement of already existing structures 79 (see Chapter 5). Due to low systemic blood pressure and high renal vascular resistance, the kidneys only receive about 3% of the cardiac output during the last trimester, 80 which sharply contrasts to the situation in adults where 25% of cardiac output passes through the kidneys. After birth, renal vascular resistance decreases (like pulmonary vascular resistance) and perfusion pressures increase resulting in a fairly rapid increase in renal blood flow. Effective renal plasma flow increase from 83 mL/min/1.73 m 2 in the term neonate to 300 mL/min/1.73 m 2 by 3 months of age. 81 In the neonate, the inner cortical and the medullary zones will receive relatively more of the renal blood flow compared to the mature kidney. Autoregulation of renal blood flow is functioning in the neonate but the lower shoulder of this pressure–flow relationship is set at a lower level (approxi - mately 50 mmHg). 82 The glomerular filtration rate is low in the term infant, then double within the first 2 weeks of life 83 but does not reach adult levels until 2 years of age. 84 The tubular function is also reduced in
CHAPTER 86 ■ Management of the Neonate: Anesthetic Considerations 1445 TABLE 86-7. Clinical Implications of the Neonatal Immaturity of Hepatic and Renal Functions Hepatic Functions 1. Dosing intervals and maintenance dosing needs to be adjusted. 2. Administer small and repeated doses of intravenous drugs and titrate to effect in order not to cause an overdose or cause an unwanted prolongation of the effect of the drug. 3. When possible monitor drug plasma levels (digoxin, antibiotics) to ensure effect and avoid overdose. 4. Use drugs with a known neonatal pharmacokinetics (morphine, fentanyl, lidocaine, bupivacaine, acetaminophen) rather than new drugs which have not been evaluated properly in neonates. Renal Functions 1. Neonates tolerate fluid restriction poorly. Keep fasting times to a minimum and start intravenous fluids early to avoid dehydration. 2. Avoid excessive fluid administration. 3. Restrict sodium administration in order not to cause hypernatremia. 4. Outside the first 24 h after birth a urine output of less than 1 mL/kg/h indicate hypovolemia or impeding renal failure. 5. The neonate will respond to furosemide but larger doses compared to adults are needed in order to induce diuresis. 6. Fluid requirements in a catabolic situation is substantially lower compared to a normal anabolic situation since the formation of new cells is very limited. A catabolic situation will also limit the neonate’s ability to excrete potassium and handle nitrogen waste products. 7. The dosing of drugs which largely depend on renal excretion will have to be reduced and if possible the plasma concentrations should be closely checked in order to avoid accumulation and side effects the neonate with a decreased ability to concentrate the urine, which is the result of a relatively lower tonicity of the medullar interstitium. Fairly rapid maturation takes place during the neonatal period with an increased capacity of concentrating the urine from twice the osmolarity of plasma in the term baby to four times at 2 months of age. 85 The neonatal kidney has a welldeveloped system for sodium reabsorption 86 but a limited capacity for excreting a sodium load. 84 The neonate responds to furosemide administration with an increase in diuresis but larger doses (1 mg/kg) compared to adults are often needed. Urine output is low immediately after birth and the neonate might only void once during the first 24 hours. Diuresis then rapidly increases to a normal value of 1 to 2.5 mL/kg/h. Urine output less than 1 mL/kg/h indicate hypovolemia (most commonly) or impeding renal failure (usually due to asphyxia, hemorrhage, or septic shock). Growth, with the generation of new cells, reduces the excretory load on the renal system, since for - mation of new cells will require water, potassium and nitrogenmetabolites. The formation of new cells will take care of a considerable amount of the normal “waste products,” since water and potassium are sequestered to form new intracellular fluid and nitrogen metabolites are used to manufacture new membrane and intracellular proteins. Thus, growth has been termed “the third kidney” and will take care of a substantial part of the normal renal “waste load.” From a phylogenetic point of view it is also reason - able to assume that the neonates renal function is tailor-made to the normal requirements of the neonatal period and, thus, it would appear illogical if the newborn would be born with borderline renal failure. It should be remembered that the growth related unloading of the renal system will only be operational in an ana - bolic situation. In a catabolic situation, for example, the immediate postoperative period or during septicemia, no or very few new cells are being made, leaving the kidneys to handle the entire waste load. As a results of the above-mentioned renal considerations, the neonate cannot easily handle either fluid or sodium overload, and poorly tolerates fluid restriction since the concentration capacity is low. Meticulous attention must, thus, be focused on fluid and electrolyte balance during the neonatal period. The excretion of drugs too is affected, especially water soluble drugs which are dependent on renal excretion. The main clinical consequences of renal immaturity are summarized in Table 86–7. Fluid and Electrolyte Balance, Caloric Requirement, and Blood Volume The total body water is substantially higher in the normal neonate (75%) compared to the adult (60%), and preterm babies have a still higher total body water content (see Chapter 5). Intra- and extracellular water represents 30 to 35% and 40 to 45% of the neonate’s total body weight, respectively. This considerable expansion of the extracellular fluid compartment is even more pronounced in the premature infant. 87 The blood volume of the normal neonate is approximately 85 mL/kg and up to 90 to 100 mL/kg in preterm infants, with consistent interindividual vari - ability (60 to 130 mL/kg) due to possible placenta-to-neonate transfusion. Since plasma volume is relatively constant (50 mL/ kg, 88 this variability depends mainly on hematocrit variability. Maintenance fluid requirements increase regularly during the first days (60, 80, 100, and 120 mL/kg/24h at day 1, 2, 3, and 4, respectively), then remain stable for the rest of the neonatal period (approximately 150 mL/kg/24 h). Caloric consumption is about 100 to 120 kcal/kg/24h, half of which is required for basal metabolic needs and the remaining for growth. 89 Since caloric requirements are closely linked to fluid intake (it is virtually impossible to supply fluid with a caloric content of more than 1 calorie per milliliter), pathological conditions where cell growth is halted (severe sepsis, postoperative period following major surgery), are at risk of metabolic overload as well as fluid retention if fluid and caloric supply are not adjusted. Daily electrolyte requirements for maintenance of electrolyte balance in the neonate are 2.5 mmol/kg, 2.0 mmol/kg, and 0.5 mmol/kg for sodium, potassium, and calcium, respectively. It should be remembered that a negative sodium balance negatively affects the growth of the neonate and can also affect growth later in life. 90 In most cases a
Page 1 and 2: Management of the Neonate: Anesthet
Page 3 and 4: CHAPTER 86 ■ Management of the Ne
Page 7: CHAPTER 86 ■ Management of the Ne
Page 27 and 28: TABLE 86-19. Typical Management of
Page 39: CHAPTER 86 ■ Management of the Ne

Chapter 86

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?