PHYSIOLOGY OF URETERO-PLACENTAL CIRCULAT

Saint John’s Medical college Bangalore. : 

3-Mar-10 1 Saint John’s Medical college Bangalore.

Department of Anaesthesiology. : 

3-Mar-10 2 Department of Anaesthesiology.

1.Physiology of Uteroplacental circulation.2.Placental Transfer of Drugs. : 

1.Physiology of Uteroplacental circulation.2.Placental Transfer of Drugs. Moderator : Dr.Elavarasi. Presented by Dr.Liyakhath Ali 18 JAN-2010 3

1.Physiology of Uteroplacental circulation : 

1.Physiology of Uteroplacental circulation Human placenta  villous haemochorial type. At term.wt 500 gm,diameter 20cm, 3 cm thick. Normal fetal to placental weight ratio ;6.1. 18 JAN-2010 4

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Fetal & maternal blood is separated by 3 structures. cytotrophoblast. syncytiotrophoblast,metabolically active, has got endocrine function.  connective tissue. 18 JAN-2010 5

Mechanism of exchange. : 

Mechanism of exchange. Substances are exchanged across the placenta by 5 mechanism. 1.Diffusion ( FA.CO2.respiratory gases,Na) 2.Active transport.(AA.Ca,Fe,water sol vitamin) a. Primary active transport. b. Secondary active transport. 3.Bulk flow. 4.Pinocytosis ( Fe). 5.Breaks. 18 JAN-2010 6

Modes of transport of molecules across placenta. : 

Modes of transport of molecules across placenta. 18 JAN-2010 7

Uterine Blood Flow; : 

Uterine Blood Flow; At term, uterine blood flow represents about 10% of the cardiac output, or 600–700 mL/min (compared with 50 mL/min in the nonpregnant uterus). 80 % of uterine blood flow normally supplies the placenta; the remainder 20 % goes to the myometrium. 18 JAN-2010 8

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Uterine blood flow is not usually significantly affected by respiratory gas tensions, but extreme hypocapnia (PaCO2 < 20 mm Hg) can reduce uterine blood flow and causes fetal hypoxemia and acidosis. Uterine blood flow lacks auto regulation (vessels are maximally dilated during pregnancy), and uterine artery flow is therefore dependent on maternal blood pressure and cardiac out put. Uterus remains sensitive to alpha-adrenergic agonists. 18 JAN-2010 9

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Determinants of uterine blood flow ; Three major factors decrease uterine blood flow during pregnancy: (1) systemic hypotension, (2) uterine vasoconstriction, and (3) uterine contractions. 18 JAN-2010 10

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During epidural anesthesia, it is unclear whether the sympathetic blockade per se alters uterine blood flow. In the absence of hypotension, epidural anesthesia does not alter uterine blood flow in laboring women or women undergoing cesarean section. : 

During epidural anesthesia, it is unclear whether the sympathetic blockade per se alters uterine blood flow. In the absence of hypotension, epidural anesthesia does not alter uterine blood flow in laboring women or women undergoing cesarean section. 18 JAN-2010 12

Effects of GENERAL ANAESTHESIA on UTERINE BLOOD FLOW. : 

Effects of GENERAL ANAESTHESIA on UTERINE BLOOD FLOW. Induction Agents; Barbiturates ; Barbiturates seem to have minimal direct effect on uterine blood flow; however, there are two indirect mechanisms by which they might reduce uterine blood flow. Propofol ; at doses of 2 mg/kg no changes in UBF from baseline. Ketamine ; Overall, the effects of anesthetic induction with ketamine on uterine blood flow appear similar to the effects of barbiturates—namely, a small effect of the drug itself and reduced uterine blood flow during the sympathetic response to tracheal intubation. 18 JAN-2010 13

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Inhalation Agents ; Usual clinical doses (i.e., 0.5 to 1.5 minimum alveolar concentration [MAC]) of halothane, isoflurane, enflurane, desflurane, and sevoflurane have little or no effect on uterine blood flow, although deeper planes of anesthesia are associated with decreased maternal blood pressure, cardiac output, and uterine blood flow. Thus, there is little reason to choose one of these agents over the other on the basis of their effect on uterine blood flow. 18 JAN-2010 14

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Ventilation ; Uterine blood flow is affected by the management of ventilation during general anesthesia. Although hypoxemia and hypercapnia per se do not alter uterine blood flow directly, marked hypoxemia or hypercapnia may reduce uterine blood flow by activating the sympathetic nervous system. The effect of hypocapnia on uterine blood flow is controversial. Stress & anxiety catecholamine release decrease UBF. 18 JAN-2010 15

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EFFECTS OF OBSTETRIC DRUGS ; Magnesium sulfate increases uterine blood flow in pregnant woman at rest and results in a modest decrease in uterine vascular resistance, as determined by Doppler, in women in preterm labor. Vasopressors (epinephrine,isoproterenol) dose dependent increase in BP,TPR,uterine vasoconstriction & decrease in UBF. 18 JAN-2010 16

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Vasopressors; ephedrine 1-15 mg i.v restores UBF BETTER than other pressors. phenylephrine20-100 mcg i.v  restores maternal BP & possibly UBF. Dopamine ,Terbutaline, Ritodrine  decrease UBF. Antihypertensives ; Hydralazine,Nitrogycerine increase in UBF,decrease in BP. Na-nitroprusideincrease UBF. Labetelol no change in UBF or fetal blood flow. CCB useful in preterm labor due uterine relaxation,verapamil should be used wt caution in uteroplacental insufficiency. Local anaesthetics ; supraclinical doses of lignocaine causes vasoconstriction, while clinical doses of lignocaine,bupivacaine,ropivacaine NO CHANGE IN UBF. Cocaine a potent vasoconstrictor significantly reduces UBF. 18 JAN-2010 17

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Umbilical blood flow ; In undisturbed fetus at term is abt 120 mL/kg/min or 360 mL/kg. Is unaffected by acute moderate hypoxia but is decreased by severe hypoxia. Innervation of umbilical cord is unknown. Umbilical blood flow is decreased by catecholamine administration,& acute cord compression . In conditions of chronically reduced umbilical blood flow there are no means to increase blood flow. 18 JAN-2010 18

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Oxygen transfer to the fetus. Oxygen has the lowest storage-to-utilization ratio of all nutrients in the fetus. Fetal O2 consumption is aprox 21 ml/min,fetus has got 2 min supply of oxygen. Irreversible ischemic brain damage occurs in 10 min. Compensatory mech in hypoxic states in foetus.1) redistribution of blood to vital organs including heart, brain & placenta.2) decreased oxygen consumption.3) dependence of certain vascular beds on anaerobic metabolism. 18 JAN-2010 19

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Factors affecting oxygen transfer from mother to fetus. Intervillous blood flow. Fetal placental blood flow. O2 tension in maternal & fetal blood. O2 affinity of maternal & fetal blood. Hb % of maternal & fetal blood. Maternal & fetal pH & Pco2 (Bohr effect). Placental diffusing capacity,O2 consumption & vascular geometry. 18 JAN-2010 20

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The oxygen dissociation curve is shifted to the left in the fetus as compared with the mother. The hemoglobin concentration of fetal blood is high (15 g/100 mL) when compared with the mother (12 g/100 mL). Hence, the higher oxygen affinity as well as the higher oxygen-carrying capacity of fetal blood benefits the fetus by increasing oxygen uptake across the placenta. 18 JAN-2010 21

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Carbon dioxide & acid base balance. CO2 crosses placenta more easily than O2. CO2 tension in fetal blood 40 mmHg,maternal 34 mmHg,pH 7.4 & bicorbonate level is close to that of mother. Bicarbonates & fixed acids cross the placenta much more slowly than CO2. 18 JAN-2010 22

METHODS OF UTERINE BLOOD FLOW MEASUREMENT; : 

METHODS OF UTERINE BLOOD FLOW MEASUREMENT; Placental perfusion can be measured in animals with the injection of radioactive microspheres. Placental perfusion can also be measured in humans by the injection of trace amounts of a radioactive-labeled substance, typically 133Xe. More recently, Doppler ultrasound measurement of uterine and umbilical arterial velocity waveforms have been used. 18 JAN-2010 23

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The ratio of the peak systolic waveform and diastolic trough of blood flow velocity (S/D) has been observed. A high S/D ratio is associated with reduced placental perfusion. 18 JAN-2010 24

2.Placental Transfer of Drugs. : 

2.Placental Transfer of Drugs. DETERMINANTS OF PLACENTAL TRANSFER. Maternal factors .UBF,Uterine contraction, supine position,maternal hypo/hypertension. Total Dose of the drug. Route & injection site. Adjuvants; epinephrine reduces peak maternal local anaesthetic concentration by 30%-50%. 18 JAN-2010 25

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Maternal tissue & protein bindingTransfer of a drug that is highly protein bound is affected by the concentration of both maternal and fetal plasma proteins, which varies with gestational age and disease. Lipid solubilityHigh lipid solubility may allow a drug to penetrate the cell membrane (a lipid bilayer) easily. Maternal metabolism & excretion 18 JAN-2010 26

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Maternal pH & pKa of the drug The pKa of a drug determines the fraction of drug that is nonionized at physiologic pH. Thus, fetal acidemia will greatly enhance the maternal-to-fetal transfer (i.e., “ion trapping”) of many basic drugs, such as local anesthetics and opioids.Most anesthetic drugs are passively transferred, with blood flow rates. Molecular size of substance (< 500 Dalton easily crosses) . Uterine blood flow 18 JAN-2010 27

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Placental factors ; The Fick’s principle governs the rate of transfer of a drug across a membrane: where Q/t is the rate of diffusion, K is the diffusion coefficient, A is the surface area of membrane available for exchange, Cm - Cf is the concentration gradient between the maternal and fetal circulation, and D is the thickness of the membrane. Placental transfer of drug Is fecilitated by high concentration of non-ionized ,lipid soluble,non-protiene bound drug. Placental uptake & metabolism of clinically used anaesthetics is very much limited. 18 JAN-2010 28

The area of human placenta is 11 m2 compared to 70 m2 of alveolar surface area of lung. Area of actual exchange (vasculo syncytial membrane ) is 1.8 m2. : 

The area of human placenta is 11 m2 compared to 70 m2 of alveolar surface area of lung. Area of actual exchange (vasculo syncytial membrane ) is 1.8 m2. Concentration gradient ;depends on following factors   Concentration of substance in maternal & fetal arterial blood. Maternal intervillous blood flow. Feto-placental blood flow. Diffusing capacity of placenta for the substance. Ratio of maternal to fetal blood flow exchanging areas. Binding of substances to molecules & dissociation rates. Geometry of exchanging surfaces with respect to blood flow. The metabolism of substance. 18 JAN-2010 29

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Fetal factors ; fetal uptake, distribution, metabolism & elimination determines the physiologic effects of a drug that has crossed placenta. Factors that determine the concentration of free drug in fetal umbilical arterial blood. umbilical venous blood concentration Fetal pH Fetal protein binding Fetal tissue up take Nonplacental routes of fetal drug elimination Fetal hepatic metabolism Fetal renal excretion. 18 JAN-2010 30

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Inhalation Anesthetic Agents ; The lipid solubility and low molecular weight of these agents facilitates rapid transfer across the placenta. A prolonged induction-to-delivery interval results in lower Apgar scores in infants exposed to general anesthesia. Placental transfer of halothane is brisk, like wise enflurane,isoflurane distributes rapidly across the placenta during cesarean section. No published data regarding the placental transfer of either desflurane or sevoflurane. 18 JAN-2010 31

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Nitrous oxide also rapidly crosses the placenta. An F/M ratio of 0.83 is expected within 3 minutes. Maternal administration of nitrous oxide decreases fetal central vascular resistance by 30%,and a prolonged induction-to-delivery interval may cause neonatal depression. Diffusion hypoxia may occur during the rapid elimination of nitrous oxide from the neonate. Therefore, it seems prudent to administer supplemental oxygen to any neonate who has been exposed to nitrous oxide immediately before delivery. 18 JAN-2010 32

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Induction Agents; BARBITURATES (thiopental & methohexital ); all barbiturates rapidly crosses placenta & equilibrium btwn mother & foetus is achieved with in minutes. When used in parturient for sedation it causes prolonged neonatal depression. High doses causes (600-1000 mg) neonatal somnolence, Flaccidity, hypoventilation & failure to feed for 2 days. Even with low doses, with near normal APGAR score, the newborn attention span may be decreased for 2-4 days. For these reasons most consider barbiturates not a good choice in parturient. 18 JAN-2010 33

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KETAMINE ; Some anesthesiologists prefer to give ketamine during the induction of general anesthesia for cesarean section, especially to patients with hypovolemia or asthma. This phencyclidine derivative rapidly crosses the placenta. Propofol ; F/M is 0.65-0.85, Propofol is highly protein bound; thus placental transfer is affected by changes in plasma protein concentrations. Increasing the fetal albumin concentration increases the total—but not the free—concentration of propofol in umbilical venous blood. Exact pharmacokinetic data not available. 18 JAN-2010 34

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BENZODIAZEPINES ; problems in the neonate, including sedation, hypotonia, cyanosis, and impaired metabolic responses to stress. Diazepam is highly unionized and very lipophilic. Fetal-maternal ratios of 1.0 are attained within minutes of maternal injection and increase to nearly 2.0 after 1 hour. Lorazepam is less lipophilic, and as would be predicted, it takes almost 3 hours after its administration for the F/M ratio to reach unity. Midazolam is even more polar, and its F/M ratio is approximately 0.76 at 20 minutes after administration. 18 JAN-2010 35

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Opioids ; All opioids crosses placenta in significant amount. Meperidine remains a commonly used opioid in obstetrics, even though it has been associated with neonatal central nervous system (CNS) and respiratory depression. Intravenous administration of meperidine is followed by a rapid transfer of the drug across the human placenta, 90 seconds after maternal administration. 18 JAN-2010 36

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Morphine also rapidly crosses the placenta. Low lipid solubility, weak protein bound ,intrathecal administration of morphine results in a high F/M ratio, Concurrent naloxone administration apparently does not affect the placental transfer of morphine. Fentanyl; highly lipid soluble, 85% protein bound, rapidly crosses placenta. 18 JAN-2010 37

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Remifentanil ; remifentanil has an extremely rapid plasma clearance and offset of action, average F/M ratio of 0.88. In some cases, administration of remifentanil has resulted in excessive maternal sedation, but no adverse neonatal effects have been observed. Thus, fetal exposure to the drug is minimized because of its rapid metabolism or redistribution, or both. 18 JAN-2010 38

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Maternal administration of alfentanil results in an F/M ratio of approximately 0.30, but it is associated with a reduction of 1-minute Apgar scores. Maternal administration of sufentanil results in a very high F/M ratio of 0.81. However, its greater lipid solubility and more rapid uptake by the CNS (as compared with fentanyl) results in less systemic absorption from the epidural space, which reduces maternal and umbilical vein concentrations and subsequent fetal exposure (and perhaps reduces the risk of neonatal respiratory depression). 18 JAN-2010 39

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Local Anesthetics Local anesthetics are weak bases; they have a relatively low degree of ionization and considerable lipid solubility at physiologic pH,hence readily cross the placenta. Ion trapping can occur with LA. In the acidotic fetus, a greater proportion of drug in the ionized form results in a larger total amount of local anesthetic in fetal plasma. 18 JAN-2010 40

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Muscle Relaxants N-M BLOCKERS are quaternary ammonium salts. These drugs are fully ionized, and they do not readily cross the placenta. When a single dose of succinylcholine is administered to facilitate intubation, it is not detected in umbilical venous blood at delivery. Some anesthesiologists have advocated the use of rocuronium as an alternative to succinylcholine during rapid-sequence induction of general anesthesia for cesarean section 18 JAN-2010 41

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Anticholinergic Agents The placental transfer rate of anticholinergic agents correlates directly with their ability to cross the blood-brain barrier Atropine is detected in the umbilical circulation within 1 to 2 minutes of maternal administration, By contrast, glycopyrrolate is poorly transferred across the placenta. 18 JAN-2010 42

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Vasopressor Agents Vasopressor agents with predominant alpha adrenergic activity reduce uterine blood flow & may affect the fetus adversely. Methoxamine,angiotensin or norepinphrine use is associated with fetal asphyxia. Ephedrine,mephentermine & metaraminol restore UBF towards normal. Ephedrine easily crosses the placenta and results in an F/M ratio of approximately 0.7. 18 JAN-2010 43

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Antihypertensive Agents Beta-adrenergic receptor antagonists are used as antihypertensive agents in pregnancy. Early studies suggested that these agents were associated with intrauterine growth restriction and neonatal bradycardia, hypoglycemia, and respiratory depression. 18 JAN-2010 44

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propranolol has F/M ratio of 0.26 after a single dose of administration. Chronic administration of propranolol during pregnancy may result in F/M ratios greater than 1.0. Other studies have noted that maternal administration of atenolol and metoprolol results in mean F/M ratios of 0.94 and 1.0, respectively. 18 JAN-2010 45

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Labetalol is combined alpha & beta adrenergic blocking agent, used for treatment of either chronic or acute hypertension in pregnant women. i.v administration of labetalol does not alter uterine blood flow in preeclamptic woman at rest nor reduce the placental perfusion. At least one study observed mild neonatal bradycardia after maternal administration of labetalol. 18 JAN-2010 46

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Some anesthesiologists favor maternal administration of the extremely short-acting beta-adrenergic receptor antagonist esmolol to attenuate the hypertensive response to laryngoscopy and intubation. Mean F/M ratio of 0.2 after maternal administration of esmolol in gravid ewes. 18 JAN-2010 47

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Clonidine and methyldopa. when magnesium and nifedipine are used therapeutically, can produce fetal vasodilation ,this is not seen with clonidine. Intravenously administered alpha-2 agonists such as clonidine causes rapid placental transfer,maternal & fetal hypoxemia, hyperglycemia & decreased heart rate. 18 JAN-2010 48

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Hydralazine is frequently used to treat severe hypertension in preeclamptic women. Fetal and maternal concentrations are similar, so the F/M ratio approximates unity. In vitro administration of hydralazine into the maternal side of a human placenta produces fetal vasodilation. Sodium nitroprusside is lipid soluble and rapidly crosses the placenta, it causes direct vasodilatation of uterine arteries more than hydralazine. 18 JAN-2010 49

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Glyceryl trinitrate (nitroglycerin) also crosses the placenta, with an F/M ratio of 0.18 observed during a study using in vitro perfusion of the human placenta. No change in,fetal umbilical blood flow, blood pressure, fetal perfusion pressure, heart rate, or blood gas measurements was noted. 18 JAN-2010 50

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Placental transfer of angiotensin-converting enzyme (ACE) inhibitors may adversely affect fetal renal function. Enalaprilat rapidly crosses the placenta; maternal administration of high doses lowered fetal arterial pressure. 18 JAN-2010 51

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Anticholinesterase Agents Neostigmine, pyridostigmine, and edrophonium are quaternary ammonium compounds that are ionized at physiologic pH; thus they undergo limited transplacental transfer 18 JAN-2010 52

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Anticoagulants Maternal administration of warfarin results in an increased rate of fetal loss and congenital anomalies. By contrast, studies have confirmed that heparin does not cross the placenta. Warfarin is contraindicated during the first trimester, and most physicians prefer the administration of LMW heparin rather than warfarin throughout pregnancy. 18 JAN-2010 53

Thank You ! : 

Thank You ! 18 JAN-2010 54