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Pre-eclampsia, which is associated with placental abnormality, can increase the diffusion distance. Molecular Weight and Spatial Configuration of Drugs Drugs between and daltons Da will freely cross the placenta. Most of the clinically useful drugs will cross the placenta because of their low molecular weight.

However, heparin, and protamine cannot cross the placenta because of their large molecular weight. Protein Binding and Lipid Solubility of Drugs Drugs bound to plasma protein cross a biological membrane like the placenta with great difficulty. Hence drugs such as bupivacaine, with its higher protein-binding capacity, will have less placental transfer. Lipid solubility eases the transfer of drugs through the placenta. Highly lipidsoluble drugs, such as barbiturates, can reach the fetus in large amounts after easy placental transfer. Diazepam is a highly protein-bound drug. Diazepam given intravenously after local anesthetic administration will compete with protein binding and will thus increase the free local anesthetic concentration.

Fetus Fetal uptake, distribution, and metabolism and elimination will ultimately be responsible for the fetal drug concentration and its effect on the fetus. Once drugs reach the fetus, several important factors will determine the free umbilical artery concentration of drugs. Uptake Fetal uptake of drugs will depend on protein binding, lipid solubility, and the pKa of the drugs. Because of lesser amount of total protein in the fetus, plasma protein-binding capacity in the fetus is less than in the mother; hence a higher amount of free drug will be available in plasma.

Normal fetal pH varies between 7. The ionized form of drugs will get trapped in the fetus since they will be unable to cross the placenta. The left lobe of the liver is transfused by the umbilical vein blood, whereas the right lobe is perfused by portal vein blood. This high uptake has also been observed with halothane, lidocaine, and cyclamate. Progressive Dilution of Umbilical Vein in Blood Concentration Umbilical vein blood going through either the fetal liver or the ductus venosus will ultimately be diluted by the blood received from the inferior extremity or gastrointestinal tract.

This diluted umbilical vein blood will be shunted through the foramen ovale of the heart and ultimately to the fetal brain. Fetal circulation numbers indicate percent saturation. From Martin R. Prepartum and Intrapartum fetal monitoring. New York, Springer, This is related to extensive shunting of the fetal circulation via the foramen ovale of the heart as well as the ductus arteriosus. This mechanism leads to diminished exposure of the fetal brain to circulating drugs. Metabolism and Elimination Although hepatic enzyme activity in the fetus is usually less than that in the adult, the human fetus can take care of the drugs administered to the mother in therapeutic doses.

Hence premature fetuses can metabolize maternally administered local anesthetics. Apgar scores, acid-base values, and neurobehavior tests have been used to observe drug effects on the fetus. Mattison DR: Physiologic variation in pharmacokinetics during pregnancy.

New York, Marcell Dekker Inc, Fetus and neonate. Morishima HO, Finster M, Pedersen H, et al: Placental transfer and tissue distribution of etidocaine and lidocaine in guinea pigs abstract. Obstetric anesthesiologists should be aware of the interactions of maternally administered drugs with anesthetic agents and techniques.

Drugs Used for Maternal Indications Antibiotics Rarely, parturients may receive antibiotics for various disease processes. Most of the antibiotics will prolong the effect of nondepolarizing muscle relaxants, but prolongation of depolarizing muscle relaxants has also been observed Table Antagonism of this action by neostigmine and pyridostigmine is found to be unpredictable; however, neuromuscular blockade from antibiotics could be reversed predictably by 4aminopyridine. The common antiepileptic drugs at the present time include phenytoin, phenobarbital, benzodiazepines, and valproic acid.

The pharmacokinetics of most of the antiepileptic drugs are altered during pregnancy. Parturients need higher amounts of antiepileptic drugs because of increased volume of distribution; hence measurement of the plasma concentration is important. Most of these drugs are metabolized in the liver and thus can interfere with the biotransformation of other drugs. The duration of action of the drugs, which are mainly metabolized by the liver, can be prolonged in parturients who are receiving antiepileptic drugs.

Used by permission. Hence, careful observation of the neonate is absolutely essential. Regional anesthesia should be the anesthetic technique of choice because there is evidence that a local anesthetic like lidocaine can be an effective anticonvulsant in therapeutic doses. Oxidative metabolism is catalyzed by the P enzyme system. Rifampicin decreased concentration of midazolam; its elimination half-life was also reduced.

Sympathetic nervous system antagonists are used for the treatment of hypertension; a-Methyldopa, reserpine, and guanethidine have been used in parturients. Depletion of norepinephrine is possible6a in such a situation, and indirect-acting agonists like ephedrine may be ineffective following hypotension. Direct-acting agonists like phenylephrine may be indicated in such a situation. Besides these antagonist agents, b-receptor antagonist drugs like propranolol can be used for therapeutic reasons. If the parturient is taking propranolol, medications that increase airway resistance, such as large doses of morphine or prostaglandin F2a PCF2a Prostin , should be used cautiously.

Calcium channel blockers with negative inotropic effects can exaggerate the depressant effect of propranolol. Propranolol will cross the placenta and can cause fetal bradycardia and hypoglycemia. Because this drug is destroyed by cholinesterase, which is also responsible for the metabolism of succinylcholine, a prolonged neuromuscular block has been described following the use of Arfonad and succinylcholine. Severe fetal bradycardia has been described when esmolol was given to the mother.

Sympathetic Nervous System Agonist Drugs Two drugs in this group that are used recreationally are worth mentioning: 1. Amphetamine is a central nervous system CNS stimulant. The minimum alveolar concentration is increased in parturients who are addicted to amphetamines. Higher doses of narcotics and inhalational anesthetics may be needed for general anesthesia. Cocaine is one of the commonly used recreational agents at the present time. It blocks the presynaptic uptake of norepinephrine, serotonin, and dopamine.

Chronic use will decrease a2-adrenergic- and presynaptic cholinergic mediated norepinephrine release. Ketamine or excessive catecholamines can cause severe hypertension and myocardial infarction. Tachycardia following cocaine use should be treated with labetalol because pure b-adrenergic agents will have unopposed a-adrenergic activity with associated hypertension. Decreased pseudocholinesterase levels may prolong the duration of action of succinylcholine. Cimetidine has been observed to slow down the elimination of theophylline. This problem can be exaggerated if the parturient receives ephedrine13 or epinephrine at the same time.

Theophylline can antagonize a nondepolarizing musclerelaxant block. Pancuronium should be used cautiously because of the possibility of supraventricular tachycardia. The intravenous administration of large doses of corticosteroids was associated with a twofold increase in serum levels of theophylline in patients who were receiving a theophylline infusion. Both cimetidine and ranitidine have been used as premedicant agents. Cimetidine binds to the hepatic microsomal cytochrome P system.

Chronic cimetidine use will decrease clearance as well as the metabolism of drugs like theophylline, benzodiazepines, morphine, lidocaine, and propranolol. Psychotropic Agents A broad range of antipsychotic drugs are available at the present time, and these drugs may be associated with multiple complex drug interactions. Three commonly used groups of drugs include phenothiazine, and butyrophenones.

Antipsychotic drugs are associated with elevation of serum prolactin levels and blocking of dopaminergic receptors. Most of the antipsychotic drugs will enhance the effect of narcotic analgesics. Central Nervous System Depressants. Antipsychotic drugs also exert an increased effect on sedative and hypnotic drugs. A study showed that chlorpromazine reduced the thiopental requirement as well as prolonged postoperative recovery following thiopental use.

Antipsychotic drugs can block the pressor effects of norepinephrine and other a-adrenergic agonist drugs. Selective aadrenergic-blocking effects of these drugs may exaggerate the effects of drugs with b-agonist activity propranolol. Some antipsychotic drugs like chlorpromazine and thioridazine do exert active anticholinergic effects: hence one has to be careful while administering anticholinergic premedications. Because of the higher incidence of hypotension when inhalational anesthetics are used in women taking antipsychotic drugs, one has to be careful when using general anesthesia in this population.

A higher incidence of hypotension has been described in women receiving chlorpromazine. Proper volume replacement and active treatment of hypotension are important. Other popular psychotropic drugs outside the three main groups phenothiazine, thioxanthenes, and butyrophenones are tricyclic antidepressants monoamine oxidase inhibitors MAOIs , lithium, and serotonin reuptake inhibitors SSRIs. Tricyclic Antidepressants This group of drugs has become very popular recently for the treatment of severe depression.

Their mechanisms of action include blocking the uptake of norepinephrine, serotonin, or dopamine into presynaptic nerve endings, thus increasing central and peripheral adrenergic tone. Tricyclic antidepressants also possess a strong anticholinergic effect. Drug interactions with tricyclic antidepressants are complex, and the obstetric anesthesiologist must be aware of the problems. Tricyclic antidepressants heighten the pressor response of direct-acting vasoactive drugs such as norepinephrine, epinephrine, or Neo-Synephrine.

Ephedrine may not be effective for treating hypotension in this group of women following regional anesthesia. NeoSynephrine, in small doses, may be necessary in such a situation. Tricyclic antidepressants will also exaggerate the response of anticholinergics and narcotics as well as other sedative and hypnotic drugs Table Monoamine Oxidase Inhibitors These drugs work by inhibiting the enzyme monoamine oxidase. Monoamine oxidase is responsible for the oxidative deamination of serotonin, norepinephrine, and dopamine Table ; thus their metabolism is disturbed by this group of drugs MAOIs. These drugs can also inhibit other hepatic microsomal enzymes.

Sympathomimetic Amines. Indirect-acting sympathomimetic drugs such as amphetamine, methamphetamine, mephentermine, metaraminol, and ephedrine can release excessive amounts of catecholamine and can be associated with severe hypertension in parturients receiving MAOI agents. Narcotic Analgesics. Severe respiratory depression, hypotension, and coma have also been described.

Because meperidine is still one of the most common analgesics used for obstetric cases, one has to be very careful if the population is receiving an MAOI. Metoclopramide has been observed to potentiate opiate analgesia. The administration of metoclopramide was associated with a Table Prolonged apnea following succinylcholine administration has been described in patients receiving MAOI agents. Interactions of lithium with a few agents used during general anesthesia are important.

Lithium can prolong the activity of succinylcholine, pancuronium,33 and barbiturates. Lithium rapidly crosses the placenta and can also affect neonates. Serotonin is an important neurotransmitter as well modulator in both peripheral and central nervous systems. Both selective serotonin receptor agonists and antagonists have been used. Some of these agents have been used for migraine headaches, vascular disorders, neuropathic pain, nausea, and vomiting.

However, SSRIs are popular mainly in the area of psychological illness, especially major depression. Because of their popularity, interactions with other medications as well as anesthetic agents are extremely important.

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Important pharmacologic interactions have been observed while treating the women with serotonergic drugs if they are taking serotonin inhibitors e. The Serotonin Syndrome The serotonin syndrome, a potentially life-threatening symptom complex, has been described with chronic use of SSRIs and interaction with other serotonergic drugs. All are related to exaggerated serotonin effects both peripherally and centrally. These medications, as well as some of their metabolites, can inhibit the cytochrome P isoenzymes.

One should carefully follow any parturient who are on chronic SSRI therapy: 1 preoperative coagulation data should be evaluated; 2 sedative effects of benzodiazepines may be prolonged; and 3 serotonergic drugs such as meperidine, pentazocine, and dextromethorphan may predispose women to serotinin syndrome.

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Because the SSRIs inhibit the cytochrome P, amide local anesthetic metabolism may be inhibited; hence, proper precautions are necessary while using higher concentrations and volumes of local anesthetic in women taking SSRIs. Exaggerated hypotension following spinal anesthesia has been reported following the use of Risperidone.

Tocolytic Drugs These drugs are commonly used for the treatment of preterm labor. They work by relaxing the uterus. Different groups of agents that have been used are I magnesium sulfate; 2 b-mimetic agents; 3 calcium channel blockers, e. Magnesium Sulfate In many institutions in the United States, magnesium sulfate has become the tocolytic drug of choice.

It might be the ideal agent for diabetic patients as well as for those with cardiac problems. Magnesium sulfate can interact with both depolarizing and nondepolarizing muscle relaxants. Obstetric cases receiving magnesium sulfate may need less general anesthetic, and they should be carefully monitored with a blockade monitor if muscle relaxants are used.

Terbutaline is favored because it is less expensive, with similar incidences of side effects. Because of their various side effects, drug interactions related to b-mimetic agents are extremely important. Central Nervous System. Cardiovascular System. Tachycardia, hypotension, and tachyarrhythmias are due to a direct effect of the drugs as well as an indirect effect from hypokalemia,which may be associated with the use of these drugs. Respiratory System. Pulmonary edema is one of the most complex problems associated with b-mimetic therapy.

Metabolic Changes. Hyperglycemia, hyperinsulinemia, and consequent hypokalemia are possible side effects. Ketoacidosis can occur mainly in diabetic parturients. Tachycardia can be worsened in the presence of other b-agonist drugs such as epinephrine, ephedrine, and parasympatholytic drugs such as atropine and can increase the chance of tachyarrhythmias.

Phenylephrine Neo-Synephrine may be indicated to treat hypotension in such cases. Halothane must be avoided if general anesthesia is used. Hypokalemia can also prolong the effect of nondepolarizing muscle relaxants. Calcium channel blockers will potentiate the myocardial depressant effect of inhalational anesthetics.

Uterine hemorrhage can be a potential problem. An important drug interaction between the Ca-channel blocker nifedipine and magnesium has been reported. Severe hypotension with cardiovascular collapse may occur. Prostaglandin Inhibitors Prostaglandin inhibitors like indomethacin can affect platelet function and can interfere with coagulation. Regional anesthesia may be contraindicated in such situations. Oxytocin antagonist, Atosiban has recently been tried as a tocolytic agent.

Nitroglycerin Nitroglycerin can be used for the treatment of hypertension or occasionally for uterine relaxation. It can affect the neuromuscular blockade produced by pancuronium. The drug interaction of trimethaphan and non-depolarizing muscle relaxants has been described. Oxytocin Oxytocin is a commonly used agent for placental expulsion and the treatment of uterine atony. Synthetic oxytocin Pitocin is associated with hypotension, whereas pitressin naturally occurring oxytocin will be associated with hypertension. Hypotension is well tolerated in healthy women because this effect is transient.

However, severe problems have been noted in women with severe hypovolemia. Synthetic oxytocin Pitocin can cause antidiuretic responses in large doses mU or more. However, in contrast to synthetic oxytocin, these agents will cause maternal hypertension by causing direct peripheral vasoconstriction. Severe hypertension with cerebral hemorrhage has been described when intravenous Methergine is administered in combination with other vasoactive drugs such as ephedrine and phenylephrine.

Transient hypertension, severe bronchoconstriction, and pulmonary vasoconstriction have been described following the use of PCF2a. Local Anesthetics Of the two groups of local anesthetics ester vs. Chloroprocaine is the ideal local anesthetic to use in the presence of fetal distress and acidosis. In this case the dibucaine number was zero. The effects of mreceptor agonist drugs such as fentanyl and morphine have also been observed to be shortened following the use of chloroprocaine. Several mechanisms have been suggested. Increased pH, with a more basic form of the local anesthetic and the effect of CO2 have been proposed.

The possibility of precipitation, especially with bupivacaine, should be kept in mind. Narcotics The use of agonist-antagonist medication either parenterally or epidurally in women addicted to narcotics can trigger an acute abstinence syndrome characterized by tachycardia, tachypnea, diaphoresis, hypotension, abdominal cramps, and agitation and apprehension. Azole is a potent inhibitor of midazolam hydroxylation and thus can increase the concentration of midazolam. Drugs Used for Fetal Indications At the present time, different agents have been used maternally to treat fetal arrhythmias.

These abnormal rhythms in the fetus are usually due to defects in the conduction system that are either anatomic or related to viral infection. Digoxin, verapamil, quinidine, procainamide, and propranolol have been used in mothers in the hope that these drugs will ultimately reach the fetus via the placenta. Important drug interactions may involve cardiogenic drugs and agents that may be used for maternal indications. Maternal plasma levels should be monitored for therapeutic digoxin levels. The plasma potassium concentration is also important because low plasma potassium levels exacerbate digoxin toxicity.

On the other hand, ephedrine might be detrimental in the presence of fetal tachyarrythmias; smaller doses of phenylephrine Neo-Synephrine may be indicated in such a situation. However, if there is associated congenital fetal bradycardia, Neo-Synephrine use should be contraindicated. Drug interactions are complex, and a thorough knowledge is necessary because various agents may be used for both maternal and fetal indications.

Annu Rev Pharmacol ; Julien RM: Lidocaine in experimental epilepsy: Correlation of anticonvulsants effect with blood concentrations. Electroencephalogr Clin Neurophysiol ; Gaffney TE, Chidsey CA, Braunwald E: Study of the relationship between the neurotransmitter store and adrenergic nerve block induced by reserpine and guanethidine.

Circ Res ; Anaesthesia ; Wilkerson RD: Cardiovascular effects of cocaine: Enhancement by yohimbine and atropine. Am J Emerg Med ; Am Rev Respir Dis ; Takaori M, Loehning RW: Ventricular arrhythmias during halothane anaesthesia: Effect of isoproterenol, aminophylline and ephedrine. Can Anaesth Soc J ; S Afr Med J ; Ann Intern Med ; Klotz U, Reimann 1: Delayed clearance of diazepam due to cimetidine. N Engl J Med ; Snyder SH: The dopamine hypothesis of schizophrenia.

Am J Psychiatry ; Jackson CL, Smith D: Analgesic properties of mixtures of chlorpromazine with morphine and meperidine. Wallis R: Potentiation of hypnotics and analgesics. Clinical experience with chlorpromazine. NY State J Med ; Moore DC, Bridenbaugh LD: Chlorpromazine: A report of one death and eight near fatalities following its use in conjunction with spinal, epidural and celiac plexus block. Surgery ; Baltimore, University Park Press, Rogers KJ: Role of brain monoamines in the interaction between pethidine and tranylcypromine.

Eur J Pharmacol ; Biochem Pharmacol ; Br Med J ; Neuropharmacology ; JAMA ; Benedetti TJ: Life threatening complications of beta-mimetic therapy for preterm labor inhibition. Clin Perinatol ; Grospietsch G, Fenske M, Birndt J, et al: The renin-angiotensinaldosterone system, antidiuretic hormone levels and water balance under tocolytic therapy with fenoterol and verapamil. Int J Gynaecol Obstet ; Hatjis CG, Swain M: Systemic tocolysis for premature labor is associated with an increased incidence of pulmonary edema in the presence of maternal infection.

Miller RD, Roderick L: Diuretic-induced hypokalemia and apancuronium neuromuscular blockade and its antagonism by neostigmine. Munsick RA: The pharmacology and clinical application of various oxytocic drugs. Abouleish E: Postpartum hypertension and convulsion after oxytocic drugs.

A review and update. J Cardiothorac Anesth ; Anesth Analg ; 67 suppl This technique recently has been banned by the World Health Authority. More recently, Doppler ultrasound measurement of uterine and umbilical arterial velocity waveforms have been used with some success. The oxygen dissociation curve is shifted to the left in the fetus as compared with the mother.

Clinical Implications of the Uteroplacental Circulation The uteroplacental circulation is directly involved with respiratory gas exchange in neonates. Umbilical blood flow velocity. Compensation takes place either by increased oxygen extraction or by redistribution of the fetal circulation. Stark et al. Vasopressin might play a role in redistribution of the fetal circulation. Maternal hypocapnia, on the other hand, will be associated with fetal hypoxia and acidosis. Mechanisms of fetal acidosis during maternal hyperventilation. Contractions can be measured by observing intrauterine pressure.

Besides this important factor. Pathological Conditions The three most important maternal pathological states that reduce the placental perfusion considerably are 1 pregnancy induced hypertension pre-eclampsia , 2 diabetes, and 3 overdue dates or postmature pregnancy. In doses of 0. Midazolam has the same effect. McCollum and Dundee compared four induction agents, thiopental, etomidate, methohexital, and propofol in equipotent doses. Animal experiments support the view that light and moderately deep anesthesia 1 and 1. Interestingly, their pharmacokinetics is similar to that of nitrous oxide, and they may be used instead of nitrous oxide.

The MAC—awake is 2. In equipotent MAC there are no differences in the degree of uterine relaxation. Blood loss and uterine tone were similar. No differences were observed in neonatal neurobehavioral outcome. Higher blood levels can also be achieved with a paracervical block, and this may be associated with severe fetal bradycardia.

Intravenous injections of 0. Epinephrine possesses both a- and b-mimetic effects on adrenergic receptors. Fifteen micrograms of epinephrine has been suggested as an intravascular test dose. On the other hand, the injection of epinephrine intravascularly will cause uterine vasoconstriction in a dosedependent manner. Use of propranolol can cause fetal 1 bradycardia, 2 hypoglycemia, 3 intrauterine growth retardation, 4 respiratory depression, and 5 hyperbilirubinemia. Maternally administered esmolol produces badrenergic blockade and hypoxemia in fetal sheep.

Also, possibly because of rapid placental transfer, esmolol can cause direct fetal bradycardia. Epidural and Subarachnoid Opiates Epidural and subarachnoid opiates, except meperidine. Hence, appropriate knowledge of uteroplacental physiology and pathology is important for the obstetric anesthesiologist. Am J Physiol ; Philadelphia, JB Lippincott, , p Prague, Acta Obstet Gynecol Scand ; Coleman AJ: An intravenous method of anaesthesia for caesarean section.

Part II. Br JAnaesth ; Anest Analg ; Baltimore, University Park Press, , p Eger EI: New inhaled anesthetics. Anesthesiology ; 22a. Etiology of fetal bradycardia following paracervical block anesthesia. Bonica JJ: Circulatory effects of peridural block. Effects of epinephrine. Ramanathan S, Grant GJ: Phenylephrine for the treatment of maternal hypotension due to epidural anesthesia. Ducey JP, Knapp KG: Maternal esmolol administration resulting in fetal distress and cesarean section in term pregnancy.

The second stage starts from full dilatation of the cervix and terminates at the time of the delivery of the infant. The third stage starts from delivery of the infant and terminates at the time of expulsion of the placenta. This can be explained by the common neuronal pool supplying both the uterus and the anterior abdominal wall Fig. These nerves ultimately communicate with the superior hypogastric nerve and reach the sympathetic chain either directly or via the aortic plexus. The nerves in the spinal cord relay to T 10 11 L 12 1 S 2 3 4 Figure Pain pathways for the first and second stages of labor.

Pain for the second stage of labor is carried by the pudendal nerve S2, S3, S4. This nerve originates from the sacral plexus and accompanies the pudendal vessels across the ischial spine where the nerve can be blocked. Relief of Labor Pain Not Related to Medication The McGill pain questionnaire ranks labor pain in the upper part of the pain scale between that of cancer pain and amputation of a digit1 Fig. Comparison of pain scores by using the McGill pain questionnaire. Adapted from Melzack R: Pain ; These techniques include hypnosis, psychoanalgesia natural childbirth and psychoprophylaxis , the Leboyer technique, acupuncture, and transcutaneous electrical nerve stimulation TENS.

Hypnosis Hypnosis has been used for long time. The advantages of this maternal and fetal physiological major disadvantage is related to rate. Psychoprophylaxis Lamaze is the originator of this psychoanalgesic technique, and it became very popular among women who tried to avoid medications during labor and delivery. The advantages of this procedure include the avoidance of any medications, which disturb the maternal physiology, as well as avoidance of fetal depression from narcotics.

However, the success rate of this technique varies considerably, and parturients may request systemic medications or regional analgesia when using this technique. Interestingly, a study shows that parturients prepared for delivery under psychoprophylaxis need less analgesia than do unprepared parturients. Hence Dr. Leboyer believes in delivering the baby in a silent semidark room and also avoiding stimulation of the newborn immediately after the delivery. In Boston Hospital for Women, Leboyer delivery was popular among a few obstetricians. Parturients received either systemic medication, local anesthetic via the epidural route, or no medication.

Anesthesiologists and neonatologists faced a few problems: 1 problems with neonatal temperature and 2 improper lighting for adequate evaluation of the babies. Acupuncture Acupuncture techniques have been used in China both for surgery as well as for pain relief; however, there is no evidence of this technique being used for pain relief of labor and delivery. Wallis and colleagues used this technique in parturients without adequate success.

Although the mechanism is not exactly known, the different hypotheses that have been put forward are 1 modulation of the pain impulse reaching the substantia gelatinosa and 2 liberation of endogenous opioids. Skin electrodes of conductive adhesive are placed over the TL1 spinal region bilaterally; TENS can also be applied in the sacral area during the second stage of labor Fig.

Because of its inconsistent success, this technique has never become popular in this country. Water Birth Another natural childbirth option that has become popular is water birth. Water birth provides a calm, relaxing atmosphere for both the expectant mother and her newborn. Melzack R: The myth of painless childbirth. Pain ; Leboyer F: Birth Without Violence. London, Wildwood House, Narcotics 2. Dissociative medications 4. Amnestic drugs 5. Neuroleptanalgesia 6. Because of their faster action and more reliable plasma concentrations, most of these agents are used intravenously.

The various narcotics that can be used are as follows: Morphine One of the most effective pain relievers, morphine used to be a popular agent; however, because of the possibility of a higher incidence of neonatal respiratory depression this agent is not popular for obstetric patients at the present time.

It is used either intramuscularly 5 to 10 mg or intravenously 2 to 3 mg , and its peak effect occurs at 1 to 2 hours and 20 minutes, respectively. It is used both intramuscularly 50 to mg and intravenously 25 to 50 mg , and its time of onset is 40 to 50 minutes and 5 to 10 minutes, respectively. Meperidine rapidly crosses the placenta and attains fetal and maternal equilibrium within 6 minutes. Relationship between the meperidine delivery interval and urinary excretion of meperidine by the neonate. Relationship between the meperidine delivery interval and urinary excretion of normeperidine by the neonate.

Recently neonatal neurobehavior change has been observed from normeperidine excreted from breast milk. This drug is not available at the present time.

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This agent can be used intramuscularly 50 to mg or intravenously 25 to 50 mg and will have its peak effect in 7 to 8 minutes and 3 to 5 minutes, respectively. It crosses the placenta, but it is rapidly metabolized by the neonate. It has been used as a continuous intravenous infusion or patient controlled infusion with some success. In one report authors used 0. Barbiturates Barbiturates are seldom used at the present time because of their adverse effects in neonates when used in high doses.

Tranquilizers Phenothiazines Hydroxyzine Vistaril and promethazine Phenergan have been used extensively in obstetric cases. Benzodiazepines These agents are effective anxiolytic, hypnotic, anticonvulsant, as well as amnestic drugs. A popular anxiolytic drug, diazepam has been used extensively in obstetric practice. In small doses 2. Sodium benzoate, which is used as a buffer in the injectable solution, can displace the bilirubin from albumin and can cause hyperbilirubinemia.

Diazepam still remains the drug of choice to treat convulsions following local anesthetic toxicity or in eclamptic patients. Because of its fast onset and short half-life this agent has become very popular in nonobstetric cases. Because of its potent anterograde amnestic effect, one has to be careful when using it for parturients. In small intravenous doses 10 to 15 mg it may be a useful analgesic drug. The possibility of delirium and hallucinations during emergence from cesarean section following large doses of ketamine may be a problem.

The use of diazepam during induction can decrease the incidence of this drawback. Other untoward side effects include hypertension, increased salivation, as well as increased involuntary movements.

Obstetric Anesthesia Handbook / Edition 5

Amnestic Agents Scopolamine hyoscine is a potent amnestic agent and also possesses mild sedative properties. Neuroleptanalgesia Innovar droperidol, 2. Agonist and Antagonist Agents Butorphanol Stadol and nalbuphine are extremely popular at the present time for the relief of labor pain. One to 2 mg of butorphanol has been found to be as effective as 40 to 80 mg of meperidine for relieving labor pain.

Nalbuphine Nubain , 10 mg intravenously, has become the drug of choice. In a double-blind randomized study using intravenous increments of nalbuphine, 3 mg, vs. A case report that included three patients was published from England. The authors used patient-controlled intravenous remifentanil for pain during labor for three thrombocytopenic parturients.

A bolus of 0. The authors mentioned that there was an initial period during which the expectant mothers learned to anticipate the next contraction and to deliver a bolus close to thirty seconds before the initiation of the contraction. They reported one episode of maternal sedation and fetal heart rate decelerations, which may have been due to excessive demand dosing; however, as the authors mentioned, mothers and neonates tolerated remifentanil without problems.

Remifentanil has a unique advantage because of its rapid metabolism by tissue esterase; hence it does not accumulate in the fetus. This is connected with a mask for use by the parturient. Parturients can self-administer this agent; however, constant communication between the woman and the administrator is absolutely vital.

However, these agents never became popular in the United States. In smaller concentrations, no detrimental effect on uterine contraction or neonates has been observed. Occasionally a high concentration of inhalation anesthetics may be necessary to relax the uterus for manipulation by the obstetrician. Major indications for these manipulations are 1 extraction of the head during a breech delivery, 2 internal version and extraction of the second baby during the delivery of twins, 3 extraction of a retained placenta, and 4 reduction of uterine inversion.

To minimize postpartum bleeding, one should immediately shut off the inhalation anesthetics following uterine relaxation. Clin Pharmacol Ther ; Shnider SM, et al: Diazepam during cesarean section—effects on neonatal Apgar scores, acid-base status, neurobehavioral assessment and maternal and fetal plasma norepinephrine levels abstract. Kanto J, Aaltonen L, Erkkola R: Pharmacokinetics and sedative effect of midazolam in connection with cesarean section performed under epidural analgesia.

Marx GF: Postpartum uterine pressure with different doses of ketamine. Frank M, McAteer EJ, Cattermole R, et al: Nalbuphine for obstetric analgesia: A comparison of nalbuphine with pethidine for pain relief in labour when administered by patient controlled analgesia. J Obstet Gynecol Br Commonw ; Interestingly, spinal opioids have physicochemical properties very similar to local anesthetics,1 as shown in Table The site and mechanism of action are different. Presynaptic and postsynaptic receptors in the substantia gelatinosa of the dorsal horn of the spinal cord have been cited as the major site of action for spinal opiates,1 whereas blockade of the axonal membrane of the spinal nerve roots and of the anterior and posterior horn cells is the mechanism of action for local anesthetics.

Physicochemical Properties of Opioids vs. There are different varieties of opiate receptors, e. The dreceptors are associated with the epileptic, behavioral, and sedative effects of opioids. Opiate receptors present in areas of the nervous system that are important for nociception and affect. Morphine, 7. The use of up to mg of meperidine was associated with adequate but a brief duration of pain relief,4 and this was also observed in the case of fentanyl. One hundred to mg of fentanyl provided quick but a short duration of pain relief. Maternal pain relief during the first stage of labor after extradural administration of 0.

At the present time, continuous infusion is used more often than the intermittent technique. The most popular mixture is the combination of bupivacaine, 0. With this dose regimen, no loss of beat-to-beat fetal heart rate variability was observed,8 and neonatal neurobehavioral scores were also found to be within normal limits. A few investigators used bupivacaine in a lower concentration of 0. The mixture of bupivacaine and alfentanil was associated with better perineal analgesia without increasing the rate of using forceps, and neurobehavioral scores were within normal limits.

However, alfentanil because of higher placental transfer can affect the neonates if it is used for a long time. Butorphanol has also been used with 0. The combination of 0. Ten milligrams of subarachnoid meperidine was tried via a gauge catheter for pain relief during labor. Intrathecal opioid mixed with local anesthetic is injected at this time. The spinal needle is withdrawn and the epidural catheter is inserted.

Sufentanil in doses of 10mg has been very effective. The addition of epinephrine did not extend the analgesic duration. The addition of 10mg of sufentanil and 2. Use of 25mcg of fentanyl mixed with 2. Cesarean Section Epidural Opiates Different epidural opioids have been used for both intrapartum and postpartum pain relief. Twenty micrograms of sufentanil was used in combination with 0. Epidural morphine 3 to 5mg has become the most popular agent for postoperative pain relief. Side effects commonly noted are pruritus, nausea, and vomiting.

A rare but important complication of intraspinal morphine is delayed respiratory depression. The incidence of this problem has been suggested to be 1 in 1, An unusual complication that has been described following the use of epidural morphine is the recurrence of herpes simplex virus infection. Epidural opioids m-agonists, e. Fentanyl, 10mg, mixed with local anesthetic will provide excellent intraoperative and a short duration of postoperative pain relief. Side effects included hypotension, nausea, and pruritus.

Addition of small doses of clonidine with morphine was found to increase the duration of postoperative analgesia as well as reduced the use of additional narcotics. Immediate and delayed respiratory depression should be treated promptly. The use of oxygen saturation, end-tidal Pco2, and apnea monitors has been advised by a number of authors. However, these devices may not be reliable in every situation; hence close nursing supervision is ideal for these patients.

Clonidine, an a-adrenergic agonist, is currently going through trials and shows promise. Four hundred to mg of clonidine provided adequate pain relief without any adverse side effects. Recently, because of the popularity as well as practicality of the CSE technique, different agents have been tried as an adjuvant to local anesthetic. Two medications that warrant mentioning are 1 clonidine and 2 neostigmine. Clonidine, a spinal alpha-2 adrenoreceptor agonist, has been tried by the intrathecal route.

In one study 0. This study found no neonatal problem according to the Apgar scores. However, the authors cautioned regarding the effect of clonidine in neonates, especially related to hypotomia and drowsiness. Since the elimination of clonidine is prolonged, these symptoms may appear within 24 hours of drug administration. The authors did not use neurobehavioral testing for neonatal outcome.


Neostigmine may be an interesting agent for spinal analgesia. The doses of neostigmine, however, must be optimal, as higher doses may be associated with nausea and lower extremity weakness. The doses as well as the optimal mixture of neostigmine, clonidine, opioids and bupivacaine are under study. For cesarean section, intraspinal opiates are associated with intense pain relief both during and after surgery.

Even with all these advantages, the side effects, especially delayed respiratory depression, remain the major problem. Ramanathan S: Obstetriec Anesthesia. Reg Anaesth ; 8. Amant MC, et al: Epidural narcotic analgesia for labor and fetal heart variability abstract.

Anesthesiology ; — Phillips G: Continuous infusion epidural analgesia in labor: The effect of adding sufentanil to 0.

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  • Ray N, Datta S, Johnson MD, et al: Low dose alfentanil versus fentanyl with bupivacaine for continuous epidural infusion for labor abstract. Reg Anaesth ; 15 suppl Reference deleted in proof. Naulty JS: Cesarean delivery analgesia with subarachnoid bupivacaine, fentanyl and morphine abstract. Reg Anesth ; 19 6 — Abboud TK, Afrasiabi A, Davidson J, et al: Prophylactic oral naltrexone with epidural morphine: Effect on adverse reactions and ventilatory responses to carbon dioxide. Fed Proc ; Kuraishi Y, Hirota N, Sato Y: Noradrenergic inhibition of the release of substance P from the primary afferents in the rabbit spinal dorsal horn.

    Brain Res ; Cigarini MD, Kaba A, Bonnet F, et al: Epidural clonidine combined with bupivacaine for analgesia in labor effects on mother and neonate. Reg Anesth ; Anesthesiology Suppl A Neurobehavior tests have become popular in recent years to observe subtle changes as well as the delayed effect of maternally administered medications.

    Although based on the PrechtlBeintema2 neurological examination, the Brazelton neurobehavioral examination is one of the most thorough tests existing at the present time. Scanlon et al. Habituation to pin prick, light, and sound are included in this study. Tone is also observed in this study by a pull to sitting, arm recoil, Moro response, etc.

    Statistical analysis for ENNS is performed by the chi-square and the Fisher exact tests, as well as by an analysis of covariant comparisons between high and low scores. The last test that has been added to the list of neurobehavioral examinations is the ABS scoring system. It mainly stresses neonatal tone and at the present time is only used for early screening of newborn activity.

    Regional Anesthesia Neonatal effects from regional anesthesia can occur mainly from two sources: 1 indirectly from reduced uteroplacental perfusion due to hypotension, which can happen from sympathetic blockade, and 2 local anesthetics or narcotics that are used in regional anesthetic techniques. Maternal hypotension is associated with fetal acidosis; however, we observed that if maternal hypotension is corrected within 2 minutes, the drop in maternal blood pressure does not affect the Apgar scores or neonatal neurobehavioral scores as determined by the ENNS scoring system. The activity level is variable, with interspersed mild startles from time to time.

    The infant reacts to sensory stimuli, but delay in response is often seen. State change after stimulation is frequently noted. A-2 The eyes are open. There is considerable motor activity with thrusting movements of the extremities and even a few spontaneous startles.

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    The infant reacts to external stimulation with an increase in startles or motor activity, but discrete reactions are difficult to distinguish because of general high activity level. Intermittent fussing does not result in a change of state. A-3 There is an alert, bright look. The A-1 A-4 infant seems to focus attention on the source of stimulation, such as an object to be sucked, or visual or auditory stimuli. Impinging stimuli may break through, but with some delay. This state is characterized by intense crying, which is difficult or impossible to break through with stimulation.

    Sleep States There is light sleep with the eyes closed, a low activity level with random movements, and startles or startle equivalents. The baby responds to internal and external stimuli with startle equivalents, often with a resulting change of state. S-2 Deep sleep with no spontaneous activity except for startles or startle equivalents, usually at regular intervals. External stimuli produce startles with some delay. State cont. During an examination, state is recorded eight times, immediately prior to each specific test. Specific Tests 1.

    The response has two components: a Local flexion of the in-volved limb withdrawal plus a generalized re-sponse characterized by trunk and limb motion, color changes, crying, etc. Only the magnitude of the local withdrawal is scored in the response category as follows: 0 No response 1 Weak or delayed response 2 Fairly brisk response, perhaps delayed, but more vigorous than 1 3 Vigorous, brisk response, easily elicited b The response decrement score is recorded as the number of stimuli required before alteration of either the local withdrawal response or the general response, whichever comes first.

    Tone Evaluation a Pull to Sitting The infant is gently pulled by his hands to the sitting position, and the movement of his head is observed. Scoring is based on the observed. The test is scored as follows: 0 Complete floppiness 1 Weak attempt to extend either hips or Continued. Specific Tests cont. The infant is observed for head turning and lip movement while supine with his head in the midline. Scoring is as follows: 0 No response 1 Lip movements only or weak, incomplete head turning 2 Full head turn toward stimulus with much lip movement even if somewhat delayed 3 Vigorous turning and sucking lip movements 4.

    Sucking is scored as follows: 0 No response 1 1 to 3 sucks 2 Strong sucks, 3 to 10 per group 3 Long periods of vigorous sucking 5. Moro Response This response is elicited by a rapid, short head drop with the infant in the supine position. Note is made of the number of stimuli required until the optimal response first occurs. The stimulus applications are repeated and counted until the optimal response is observably changed. Placing With the infant in the upright position, the leg is raised until the dorsum of the foot touches a protruding bassinet edge.

    Scoring is based on flexion of the stimulated leg and placing of the stimulated foot on the edge as follows: 0 No response 1 Minimal flexion and extension of leg; foot not placed 2 Full response, difficult to elicit, foot placed Continued. Alertness This is a composite, more subjective score that includes the most alert periods during the entire exam.

    Assessment is scored either Abnormal, Borderline, Normal or Superior. The reasons for putting an infant into this category, such as which scores or tests made up the assessment, are noted. The dominant state score is entered, and the number of state changes is recorded as the lability. The comment space is used to describe any unusual aspect of the examination, any untoward events or interruptions, and such difficult to-quantitate variables as body color changes and abnormal movements. Early treatment of maternal hypotension is important and becomes absolutely essential in a situation in which there is already decreased placental perfusion diabetes, preeclampsia, postdate pregnancy, etc.

    However, subsequent studies using the ENNS as well as the ABS scoring systems did not note any changes in neonates following the use of lidocaine or mepivacaine for epidural anesthesia. There are several studies that observed the effect of other local anesthetics like bupivacaine, 2-chloroprocaine, and etidocaine and detected no adverse neurobehavioral scores following either vaginal delivery or cesarean section12 Table Spinal and General Anesthesia Hodgkinson and colleagues compared neonates whose mothers received either spinal anesthesia with tetracaine or general anesthesia with induction agents such as thiopental and ketamine.

    Lidocaine, ence with any vs. Chicago, Mosby Year Book, Merkow and colleagues observed neonatal neurobehavioral effects following bupivacaine-, mepivacaine-, and chloroprocaine-induced pudendal blocks. The implication of this difference is unknown at the present time.

    Intrathecal Narcotics Epidural and subarachnoid narcotics combined with local anesthetics have become a popular technique for both labor and delivery including cesarean section. The combination of narcotic and local anesthetic has been associated with a faster onset of pain relief, intense sensory anesthesia, as well as postpartum pain relief.

    Morphine, fentanyl, sufentanil, and alfentanil have all been used successfully. Brazelton compared neonatal breastfeeding ability as well as weight gain in infants whose mothers received either less than 60 mg or more than mg of barbiturates. Kron and colleagues also observed a decrease in both sucking ability as measured by sucking pressure and volume consumed by infants whose mothers received mg of secobarbital when compared with the control group.

    Various studies have observed its neonatal effects following maternal administration. EEG patterns were observed during olfactory, visual, tactile, and auditory stimulation. The authors noticed an alteration in the EEG tracing only during auditory stimulation in the neonates whose mothers received meperidine. Kron and colleagues observed less effective sucking in the neonates whose mothers received meperidine as compared with mothers who inhaled nitrous oxide for the relief of labor pain. When the NBAS neurobehavior assessment score scoring system was used, no differences were observed among the groups until the third day postdelivery, when the authors found an impaired habituation to ringing in the neonates whose mothers received meperidine during labor.

    Unfortunately, the importance of this isolated difference is not known. Borgstedt and Rosen examined both the EEG patterns and the Prechtl-Beintema scoring system in two groups of neonates 1 those whose mothers did not receive any systemic medication and 2 those whose mothers received morphine or meperidine with phenobarbital or promethazine. The majority of the babies had drug-related EEG changes when compared with the unmedicated group. Using butorphanol or meperidine in parturients for pain relief in labor, Hodgkinson and colleagues did not observe any differences in ENNS values between the two groups of neonates.

    Others have tried the administration of intramuscular naloxone to infants immediately after delivery, and this technique improved ENNS scores. General Anesthesia Intravenous Agents The effect of general anesthesia on neonatal neurobehavioral scores depends upon several factors, e.

    Forgot password? Forgot username? View Access Options. Advanced Search. Obstetric Anesthesia Handbook. Dean, M. Article Information. Reviews of Educational Material. Anesthesiology 6 , Vol. You will receive an email whenever this article is corrected, updated, or cited in the literature. You can manage this and all other alerts in My Account. You must be logged in to access this feature.

    By Sanjay Datta. Pages: The fact that the text has only one author allows for very little redundancy, as is often found in books written by several authors. There are a reasonable number of graphs and tables to supplement the text, and appropriate clinical pearls are italicized in each section to highlight the important aspects of each area. Datta's handbook is outlined in a very readable fashion beginning with a chapter on maternal physiology during pregnancy, labor, and postpartum. The next three chapters focus on maternal and perinatal pharmacology, emphasizing local anesthetics and drug interactions during pregnancy.

    The chapter on local anesthetics is concise and clinically useful, particularly to training practitioners. Uteroplacental circulation with an emphasis on the implications of those pharmacologic agents that alter blood flow is addressed in chapter 5. Datta focuses on labor and delivery in the next six chapters, including a review of nonpharmacologic options as well as systemic agents for labor analgesia. Fetal monitoring and the long-term effects of a variety of analgesic techniques on neonates are included. State of the art options for regional anesthesia for labor are described in chapter 11, including a thorough summary of potential complications.

    An elementary review of the anatomy of the epidural space and the site of action of anesthetics is very clear to the novice provider. Advantages and disadvantages of spinal, epidural, and general anesthesia for cesarean section are outlined and their techniques clearly summarized in the subsequent chapter. Chapter 13 is devoted to high-risk pregnancy. The chapter begins with advise on managing regional and general anesthesia for high-risk conditions. This extensive section is subdivided to include descriptions of hemorrhage, pregnancy induced hypertension, diabetes, cardiac and respiratory disease, neurologic problems, malpresentation, prematurity, multiple gestation, and a variety of other miscellaneous disorders.

    This chapter discusses a broad array of obstetric conditions addressing the anesthetic implications and guidelines for their management.