Spinal Opioids and the Treatment of the Obstetric Patient with Cardiac Disease

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It was not all that long ago that the concept of therapeutic analgesia was limited to either intravenous narcotics or the application of local anesthetics to the nerve itself. Prior to 1931, the duration of analgesia was limited to the action of the agent itself; repeated injections were the only choice if analgesia was to be protracted. Repeated injections oflocal anesthetics were painful and not always practical, and repeated intravenous injections of narcotics, though technically simple, incurred the undesirable side effects of sedation, nausea, vomiting, and respiratory depression. These could have a particularly negative impact on patients with abdominal incisions and in those in which coughing, deep breathing, and vigorous postoperative pulmonary toilet were mandatory. In 1931 the first use of continuous epidural analgesia using a ureteral catheter came into being. In 1949, it was demonstrated that the employment of epidural analgesia for postoperative pain allowed early ambulation. In 1956 it was recommended to utilize continuous epidural analgesia with local anesthetics for relief from postoperative pain. The threshold of modern pharmacologic analgesia was crossed in 1979 when Wang used 0.5to1.0 mg ofintrathecalmorphine for the successful relief of pain. OPIOID RECEPTORS It was the discovery of endogenous opioid receptors that first prompted researchers to experiment with exogenous opioid administration. They were found to be located in areas of the brain that were involved with perception, integration, and response to pain. These areas include, among others, the periaqueductal gray matter of the brain stem, the amygdala, corpus striatum and hypothalamus, and in the spinal cord, the substantia gelatinosa (Rexed' s lamina II and III) and lamina V as well. The anatomic locations of these receptors are reflected in the results of exogenous opioid administration. The analgesia is *Assistant Professor of Anesthesiology, Northwestern University Medical Center; Assistant Professor of Obstetrical Anesthesia, Prentice Women's Hospital, Chicago, Illinois f Professor of Anesthesiology and Obstetrics and Gynecology, Department of Anesthesia, Baylor College of Medicine, Texas Medical Center; Director, Obstetrical Anesthesia, Lyndon Baines Johnson Hospital, Houston, Texas

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Table 1.

III

Opiate Receptor and Response*

OPIATE RECEPTOR SITE

Medullary and pontine respiratory centers Thalamus Lateral thalamus Medial thalamus (receptor density greater in medial thalamus) Substantia gelatinosa (dorsal horn of spinal cord) Solitary nuclei Area postrema (chemoreceptor trigger area) Amygdala Gastrointestinal tract

PHYSIOLOGIC AND PHARMACOLOGIC RESPONSE

Respiratory depression Discrete, localized pain Poorly localized, deep pain First site in CNS for integration of sensory information (analgesia achieved) Depression of cough reflex; orthostatic hypotension Nausea and vomiting Emotional behavior, euphoria Decreased motility (constipation)

Adapted from Snyder SH: Opiate receptors in the brain. N Engl J Med 296:266, 1977.

primarily due to the receptors found in the spinal cord. The brain stem receptors are located near the respiratory control centers and the chemotactic trigger zone, hence the frequency of the side effects: respiratory depression, nausea, and vomiting. The receptors in the hypothalamus are responsible for the narcotic effect on body temperature. The more that is known about the opioid receptors, the more complex the facts become. There are currently five categories of receptors. These include mu, kappa, sigma, delta, and epsilon. Only mu and kappa have analgesia as one of their resultant responses. Researchers have divided the mu receptor into two fractions. The mu-1 receptor is the mediator of analgesia. The mu-2 receptor is responsible for the unwanted side effects of respiratory depression, decreased heart rate, pruritis, physical dependence, and nausea and vomiting. The opioid agonist-antagonist drugs, such as butorphanol, pentazocine, and nalbuphine, antagonize the opioid responses of the mu receptors (both analgesia as well as the undesirable side effects, but they also produce analgesia of their own as a result of kappa receptor stimulation. There is also a relatively slight activation of the sigma receptor as well, but its effects are not evident clinically. Among the opioids themselves, there is a marked variation in receptor site affinity (Table 1). Morphine is a highly ionized, water-soluble narcotic. Its receptor site affinity is exceeded by the more lipid-soluble narcotics. Those with marked receptor affinity are the phenylpiperidine-related narcotics, that is fentanyl, sufentanil, alfentanil, and especially lofentanil. When given in microgram doses, their durations of action vary from 5 hours for fentanyl to 11 hours for hydromorphone (as opposed to 18 to 24 hours for morphine, which has the longest duration of all). Just as with chronic intravenous narcotic administration, tolerance to the effects of spinally administered narcotics will develop after about a week. Crosstolerance occurs between the opioids just as it does with those given systemically. Fortunately, tolerance to the antagonists (naloxone) does not occur. The complexity of the spinal cord receptors is evidenced further by the fact that there are at least four systems, the opioids being just one, that may modulate nociceptive stimuli. The other three are represented by the exogenous agents ketamine, baclofen, and ST-91. Careful substitution from one class of drug to another over a short period may allow the clinician to provide long-term pain relief and successfully avoid the problem of tachyphylaxis to any one system.

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The beauty and value of spinally administered narcotics, when contrasted to the local anesthetics, is their selective analgesia. Motor function and proprioception, unlike the effects of conduction anesthesia, are left intact. With narcotics, there is no pharmacologic sympathectomy, nor, as mentioned earlier, is there motor impairment; therefore vascular tone and ambulatory ability are preserved. This is so because the local anesthetics block the sodium channel in the membrane of the axon, thus preventing the propagation of neurologic impulses of all kinds. They act primarily on the spinal nerve within the dura. It is true that the more dilute concentrations may spare the motor impulses transmitted by the thickly insulated A-alpha fibers, but the thinly myelinated preganglionic sympathetic fibers are the most sensitive of all; a sympathectomy is therefore unavoidable with each and any local anesthetic blockade in the neuraxis. Mechanism of Action Both the body's endogenous ligands (endorphins) and the exogenous opioids commonly used for analgetic purposes act in a dose-dependent, stereospecific manner on the mu l and mu 2 receptors found throughout the central nervous system and the neuraxis. The levorotatory form of the narcotic is its active configuration, and furthermore its existence in an ionized state would appear to be a prerequisite for strong binding to the receptor's anionic site. The affinity of a given opioid or narcotic agent for the receptor is proportional to its analgesic potency. The mechanism of action has both a pre- and postsynaptic component. Fundamental to both is an inhibition of adenylate cyclase activity as a direct consequence of receptor activation. Presynaptically, opioid receptor activation results in a decrease in the release of such neurotransmitters as norepinephrine, dopamine, substance P, and acetylcholine. The depression of central nervous system cholinergic activity may prominently figure in the engendering ofboth the analgesia and the undesirable side effects commonly associated with opioid administration. Opioids also may interfere with postsynaptic transmembrane ionic calcium transport. 61 Other Inhibitory Systems To reinforce our appreciation for the complexity of the modulation, modification, and transmission of pain within the spinal cord, other pain-inhibitory substances have been discovered. Subarachnoid injections of the following substances have resulted in spinal analgesia: norepinephrine, serotonin, baclofen, midazolam, clonidine and ST-91 (an alphaz-adrenergic agonist). These represent different nociceptive inhibitory systems, which do not act through a common pathway but act independently of each other; the analgesic effects tend to be additive and complementary to each other. Tolerance within a given system may occur, just as it does with the opioids, but cross-tolerance between systems does not occur. This will allow for chronic spinal analgesia in chronic pain patients by switching from one inhibitory system to the next, or to use two or more systems simultaneously but in low doses of each, to avoid or minimize the occurrence of tolerance with chronic administration. Fundamental Principles of Spinal Opioid Administration The narcotics used in spinal analgesia today can be thought of in two groups, based on their solubility in water. The first group is represented by the highly water-soluble (and therefore relatively fat-insoluble) morphine. Its hydrophilic nature retards its penetration both through the dura (when given epidurally) and ultimately into the spinal cord itself, leaving a large reservoir of "uncommitted" molecules behind in either the subarachnoid or epidural space. This pharmacoki-

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netic property accounts for its slow onset and long duration (18-27 hr). The morphine reservoir in the epidural space is absorbed in part by the epidural venous plexus, and accounts for the fact that peak plasma levels of morphine after intramuscular or epidural injection are similar. It is these plasma levels of morphine after epidural injection that are responsible for the respiratory depression that occasionally is seen within the first several hours after epidural administration. Unlike intramuscular morphine, the degree of analgesia, as reported by the patient, correlates poorly with peak plasma levels. Analgesia is proportional instead to the concentration of opioid in the CSF. With morphine, the persistently significant amount remaining in the CSF is slowly transported rostrally, raising the level of analgesia, and resulting in the side effects of itching, respiratory depression, and nausea many hours after the injection. These are a consequence of morphine acting on the opioid receptors in the brain stem and cortex. Quite the opposite is observed with the lipophilic opioids such as meperidine, methadone, fentanyl, and particularly sufentanil and lofentanil. Because of the molecular weight and lipid solubility, these agents will rapidly penetrate the dura, the arachnoid granulations, and the pia mater to enter into the spinal cord. Very little of the drug will linger in the CSF, so that rostral progression is not a significant factor in the pharmokinetic model. However, the concentration of the drug in the epidural space is reduced by substantial vascular absorption into the epidural veins, thus rapidly reducing the concentration gradient. This vascular uptake is greatly enhanced by anything that increases venous flow and epidural pressure, such as the gravid uterine compression of the inferior vena cava. The egress of drug from the receptor area also will be equally rapid, aided by vascular uptake at the level of the arachnoid granulations. Therefore, the net result is that the analgesia will be rapid in onset, of modest duration (2-5 hr), and somewhat independent of the specific degree oflipid solubility of a given agent. Lofentanil is rather the exception: its long duration may be due to nonspecific binding to spinal cord lipid combined with a higher affinity for the mu receptor. The side effect of itching is not uncommon with the lipid-soluble agents, but respiratory depression is very rare. Finally, as is true with systematically administered narcotics, reversal with naloxone is possible. To our benefit, the higher blood flow to the brain (as opposed to the spinal cord) means that more of the dose of naloxone reaches the central opioid receptors, which are responsible for the undesired side effects; less naloxone reaches the receptors of the spinal cord, from which emanates the analgesia. This means that the undesirable side effects are reversed by low levels of naloxone while the analgesia is left intact. Only at higher doses is the analgesia compromised. CARDIOVASCULAR CHANGES DURING PREGNANCY The changes in the cardiovascular system that are seen with pregnancy constitute a stress to even a normal healthy heart. A heart that is compromised by malformation or disease may not be able to tolerate the added stress, and ventricular failure will result. With normal pregnancy, there is an increase in intravascular volume that is proportional to the size of the products of conception. Thus it is greater for twins than for singleton pregnancies. The increase in plasma volume outdistances the increase in red cell volume, hence the dilutional anemia of pregnancy. Myocardial contractility, stroke volume, cardiac output, and oxygen demand all progressively increase with gestation. An initial increase in heart rate is observed, but heart rate returns to normal at term. Ventricular compliance increases to accommodate the increase in end-diastolic volume, so that there is no increase in

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pressure. Total body sodium increases secondary to an increase in aldosterone production, such that in the healthy patient at term, there is a net fluid gain of 2 liters; in the edematous patient it may be as much as 5 liters. Blood pressure is slightly reduced with gestation. Owing to hormonal influences, both pulmonary and systemic vascular resistances (PVR and SVR, respectively) decrease. In labor, the stress, pain, and anxiety all serve to increase the level of catecholamines. The myocardial oxygen demand increases significantly. As the uterus contracts, it rhythmically injects its blood volume (500 ml) into the venous circulation, thus increasing ventricular preload and hence myocardial contractility and cardiac output. Afterload is dramatically increased. Cardiac output is at its highest (80 per cent above prelabor levels) during the third stage, as the uterus is involuting. Generally, it takes about 2 weeks for the cardiovascular system to regain its prepregnancy parameters. Pregnancy and Cardiac Disease Because of medical advances and more women having children in their later years, the frequency of the pregnant patient with cardiac disease has recently increased. Most of the diseases are a consequence of congenital anomalies or rheumatic heart disease. Generally speaking, wide ranges of involvement and severity exist. For the woman with minimal symptoms who has tolerated her pregnancy well, and whose cardiac status has been well documented, the anesthetic approach can be in the usual fashion with the customary monitoring. Those who present with signs and symptoms of severe disease with cardiac embarrassment will require a careful, well-planned obstetric and anesthetic management plan with an arterial line and invasive central monitoring. This discussion will address congenital cardiac anomalies that involve intraand extracardiac shunting, and those pathologic conditions in which preservation of systemic vascular resistance (SVR) is critical. For other lesions, such as aortic and mitral regurgitation, a well-managed epidural anesthetic using conventional local anesthetics (with their attendant sympathectomy) is of incontestable value and shall not be pursued further at this time. Tetralogy of Fallot Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, and constitutes a classic right-to-left shunt. When the degree of shunting increases less blood flows through the pulmonary circulation, the cyanosis worsens. TOF comprises of a ventricular septal defect (VSD), right ventricular hypertrophy, an overriding aorta, and right ventricular outflow obstruction, either due to infundibular hypertrophy or to fixed pulmonic stenosis. Pregnancy exacerbates the clinical condition of the uncorrected TOF by decreasing the SVR and potentially increasing the degree ofright-to-left shunting and cyanosis. The risks of bacterial endocarditis, cerebral thrombosis, and left-heart failure are increased as well. Labor and the postpartum period are also hazardous. The stress oflabor may increase pulmonary vascular resistance (PVR) and thus shunting, as may the fall in SVR. If the pulmonary outflow obstruction is due to infundibular hypertrophy, then (as in the case ofIHSS) increases myocardial contractility and decreases in right ventricular volume (preload) are to be avoided. If the obstruction is due to pulmonary stenosis, then contractility should be maintained. General principles of management for labor and delivery concern the balance of the resistances of the two vascular beds. To be avoided at all costs are decreases in SVR, increases in PVR, decreases in blood volume, venous return, and myocardial contractility (unless infundibular hypertrophy exists). Episodes of hypotension due to decreases in SVR are best treated with a direct-acting

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alpha agonist such as phenylephrine; ephedrine may cause an increase in PVR as well. These patients traditionally have been managed with systemic medication, inhalational analgesia (nitrous oxide may increase PVR) and paracervical and pudenda! blocks. Analgesia is important for several reasons, not the least of which being the avoidance of the cyclical hyperventilation pattern seen in response to painful uterine contractions. During hypoventilation, arterial oxygen content may fall to such an extent as to cause an increased PVR. Epidural analgesia with local anesthetics, if employed, must be done with extreme caution, being titrated in slowly to minimize decreases in SVR, and only after adequate prehydration. Ventricular and Atrial Septal Defects These two lesions are the two most common causes of intracardiac left-toright shunting. Patent ductus arteriosus (PDA) is a frequent cause of extracardiac left-to-right shunting. As with any other cardiac lesions, there is a spectrum of severity, the degree of which is proportionate to the size of the defects. Large defects allow for more blood to be recycled back through the right ventricle and pulmonary circulation, and finally yet again to the left ventricle. Depending on the size of the defect and amount of shunted flow, the pulmonary circulation may, by decreasing its resistance, accommodate the increased volume without a concomitant increase in pulmonary artery (PA) pressure. This is the early phase. If the defect remains uncorrected, in time the pulmonary circulatory bed will lose its ability to tolerate the perpetually increased intravascular burden. An increase in PVR is the unavoidable consequence, which gradually approximates and ultimately may exceed the SVR. Not only is shunt flow a measure of the relative balance between SVR and PVR, but in the end stage, with fixed elevated PA pressures and PVR, the shunt flow actually will be reversed, mimicking the hemodynamic picture of TOF. An Eisenmenger's syndrome now exists, with fixed pulmonary hypertension, right-to-left shunting through a septal defect, and peripheral cyanosis. Ultimately, the increased volume load takes its toll on the left ventricle. As it fails, the pulmonary hypertension is exacerbated and in time the right ventricle will fail as well. Obstetric and anesthetic management for parturients with septal defects is biphasic in its approach. If the PVR is not yet in excess of the SVR, then a left-to-right shunt exists. Increases in SVR, PVR, and HR are poorly tolerated. Labor analgesia may be provided by lumbar epidural analgesia using local anesthetics. If, however, the severity of the clinical condition is such that the PVR is high enough to reverse the shunt, then decreases in SVR also must be avoided. Patent Ductus Arteriosus Patent ductus arteriosus follows much the same principles as do septal defects. The degree ofleft-to-right flow depends on the size of the ductus: lesions greater than I to 2 cm will have significant flows. Once again, the left ventricle suffers under an increased volume load and ultimately may fail. Pulmonary hypertension gradually ensues as pulmonary resistance increases in rebellion to the increased intravascular volume. Although the shunt flow is still left-to-right, decreases in SVR tend to be salutory. When, with rising PVR, the flow through the ductus is reversed, then increases or decreases in SVR are poorly tolerated. Biventricular failure, shy of surgical intervention, is the ultimate consequence. The stress oflabor and the increases in intravascular volumes associated with pregnancy and parturition are poorly tolerated, as both tend to increase pulmonary hypertension. A failing ventricle may need inotropic support. With a leftto-right shunt, conduction anesthesia with its chemical sympathectomy is beneficial. Under general anesthesia, an infusion of phentolamine may be useful to

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avoid increases in SVR. If the severity is such that a right-to-left shunt has occurred, however, then, as with septal defects, decreases in SVR are to be avoided. Under these circumstances, as before, epidural analgesia is extremely hazardous. Coarctation of the Aorta The incidence of this disease appearing in the obstetric population has been steadily decreasing, owing to early surgical intervention. Nevertheless, there is an increase in the incidence of congenital heart disease in the offspring. An uncorrected coarctation, like aortic stenosis, represents of fixed obstruction to left ventricular outflow. Thus, increases in heart rate and not stroke volume are the only means of compensation for decreases in SVR, to maintain perfusion of tissues distal to the coarctation. Concentric hypertrophy of the left ventricle occurs, and ultimately left ventricular failure will result. In addition, pathologic changes occur in the aortic wall at the site of the coarctation, serving then as a nidus for dissection and rupture. Pregnancy, with its increases in metabolic demand and increased intravascular volumes exacerbates both ventricular failure and aortic dissection. Increases in heart rate occur as the only means available to raise the cardiac output. During periods of great oxygen demand, such as labor, the increases in heart rate may prove inadequate, and myocardial failure will be the end result. Furthermore, the decreased SVR of pregnancy also may not be well tolerated, because stroke volume is fixed. Because decreases in heart rate and SVR are poorly tolerated, intravenous isoproterenol (or atropine) given concomitantly with an intravenous infusion of metaraminol may be necessary. To maintain an adequate albeit fixed stroke volume, adequate preload is necessary, and hypvolemia therefore to be avoided. Dysrhythmias must be treated promptly. Analgesia for labor and delivery generally excludes the employment of conduction analgesia and relies rather upon systemic medication, inhalational analgesia, and paracervical and pudenda! blocks as with TOF. Aortic Stenosis Aortic stenosis can be either congenital or acquired from rheumatic heart disease. The spectrum of severity is governed by the size of the stenotic valve. Stenotic narrowing to less than 1 cm 2 markedly increases left ventricular end-diastolic pressures, and below 0. 75 cm 2 the symptoms of syncope, chest pain and dyspnea occur. A pressure gradient of 50 mm Hg may exist in severe cases not yet compromised by left ventricular failure. Much like congenital coarctation of the aorta, stroke volume is both fixed and vulnerable to decreases in end-diastolic volume (such as might occur with loss of intravascular volume (decreased pre load) or heart rates in excess of 140 beats per minute (bpm). Bradycardia or tachycardia above 140 is poorly tolerated. The maintenance of SVR by ephedrine or metaraminol infusion may be necessary, as perfusion of peripheral beds, including the coronary circulation, will otherwise be compromised. These patients tend to tolerate the stresses of labor and delivery well, and regional obstetric nerve blocks or intravenous analgesia may be sufficient. Conduction blockade should be performed carefully to avoid decreases in SVR. Primary Pulmonary Hypertension PPH is an idiopathic disease primarily found in young women and has been defined by the existance of PA pressures in excess of 30/15 mm Hg, and a mean PA pressure of greater than 25 mm Hg. The pulmonary artery occlusion pressure

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(PAOP) is normal, but the cardiac output is low and :6.xed. With time, the right ventricle will fail under an increasing workload. Of paramount importance in the management of these patients under any set of circumstances is to avoid stress and an excess of catecholamines, metabolic acidosis, hypoxemia, and hypercarbia (some of which are a natural consequences oflabor), all of which will exacerbate the pulmonary hypertension. Decreases in right ventricle preload, myocardial contractility, and SVR are additionally important to avoid. Traditionally, the methods employed for the above stenotic lesions have been employed. In 1982 Sorensen59 reported the successful use of lumbar epidural with 0.5 per cent bupivacaine (without epinephrine) for labor analgesia in a parturient. Abboud et al. 3 in 1983 reported the bene:6.ts of 1.0 mg of intrathecal morphine in 7.5 per cent dextrose for labor analgesia, with a pudenda! block for delivery. It should be pointed out the hazards of extensive use of local anesthetics, such as might be found in epidural anesthesia for surgery, where, after 400 mg oflidocaine, plasma blood levels of 4 µg per ml can cause peripheral vasodilatation and mild depression of myocardial contractility, both of which would be hazardous to these patients. Asymmetric Septal Hypertrophy (ASH) This lesion, also known as idiopathic hypertrophic subvalvular stenosis (IHSS), falls under the heading of cardiomyopathy and is characterized by muscular hypertrophy of the interventricular septum and the aortic outflow tract. Pregnancy can exacerbate this condition, placing the mother at risk for supraventricular dysrhythmias or left ventricular failure, or both. Puring ventricular contraction, the hypertrophied muscle constricts as well, and this further reduces the outflow tract. Agents or circumstances which increase contractility will do it globally, and the outflow tract is reduced further, compromising cardiac output and risking left ventricular failure even more. Therefore, the stress oflabor, with the increased myocardial contractility due to catecholamine excess, is detrimental to these patients. It is also commendable to avoid decreases in left ventricular diastolic volume; a small cavity is made smaller still when it is nearly empty, and outflow constriction will be increased. Finally, decreases in SVR may reflexively cause an increase in ejection force and exacerbate the obstruction. The management then would include myocar<:lial depressive agents, analgesia to reduce catecholamine levels but not SVR, and adequate hydration with volume replacement. Rapid heart rates, which would otherwise co1Ppromise left ventricular :6.lling, are best avoided as well. Again, the time-honored tradition has been systemic or inhalational analgesia with paracervical and pudenda! blocks. In a recent abstract, Minnich et al. 42 describe the successful use of epidural analgesia with 0 .125 per cent bupivacaine and fentanyl 5 µg per ml for labor and delivery. A pulmonary artery catheter was used to follow central cardiac parameters. Minimal changes in cardiac index and PAOP were note<:l, and the 18-year-old mother tolerated the procedure well. PREGNANCY-INDUCED HYPERTENSION (PIH) Unlike the above congenital anomalies, PIH is unhappily common, averaging about 7 per cent of all pregnancies. For all its frequency of occurrence and despite its extensive scienti:6.c de:6.nition, its etiology remains obscure and its 1Panagement controversial. At term, the preeclamptic mother usually is depleted of her intravascular volume, with an elevated SVR to maintain blood pressure and perfusion, and a

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left ventricle with an elevated cardiac output. PA pressures and to be normal. Whether analgesia is in the obstetric management of these patients is one of the main areas heated controversy exists. Proponents of epidural analgesia point out a more stable hemodynamic course throughout labor and delivery. Under the circumstances of cesarean section, the potentially disastrous consequences of the hypertensive response to both intubation and extubation are avoided. Detractors question the wisdom of giving large volumes of intravenous fluid to patients with elevated SVRs and potentially "leaky" pulmonary capillaries, thus placing them at risk for pulmonary edema. Suffice it to say that if epidural analgesia for labor is agreed on, it must be done slowly and incrementally, with the monitoring of central venous pressures to guide fluid therapy. Decreases in SVR secondary to local anesthetic sympathetic blockage are, strictly speaking, not absolutely unavoidable, but they can be minimized by such a technique.

LOCAL ANESTHETICS VERSUS SPINAL OPIOIDS Like most things in medicine, local anesthetics and narcotic agents have their particular advantages and disadvantages. Local anesthetics, in high enough concentrations, may result in a motor block with muscle relaxation. They can provide profound analgesia for both somatic and visceral pain. Their actions and durations are predictable, and they lack the side effects associated with spinal narcotics. They also can be applied along the length of nerve as well as centrally. They have potential central nervous system and cardiac toxicity if unintentially injected intravascularly. An excessively high level of block can cause respiratory embarrassment. A decrease in SVR from a chemical sympathectomy, as well as decreases in blood pressure, and possibly decreases in heart rate (if the cardioaccelerator nerves (Tl -T4) are blocked). Plasma levels may be sufficient to cause a mild depression in myocardial contractility. Central venous pooling with reduction in preload occurs to varying degrees. There are no known antagonists to the local anesthetics. Spinal opioids produce selective spinal analgesia without concomitant synpathetic, proprioceptive, or motor block, and in that lies their great strength. They, like local anesthetics, can be administered either as a single bolus or as an infusion. Their side effects include respiratory depression, both early and late, pruritis, urinary retention, sedation, nausea, and vomiting. Tolerance will develop with prolonged use. A specific reversal agent, naloxone, exists, with which undesired side effects may be antagonized. Their employment, especially with the use of morphine, necessitates more intense observation over the following 24 hours, which may restrict recovery room beds, and create more nursing obligations. Synergism has been documented between the local anesthetics and narcotics, especially between bupivacaine and morphine. Meperidine may act on both the narcotic receptor and the sodium channel of axonic membrane. For all of the preceding pathologic states, the one common entity to be minimized or avoided was a decrease in SVR. With analgesic strength concentrations of local anesthetics, this has been virtually impossible. Now, with the advent and flourishing of the numerous spinal opioids available, we are able to offer the benefits of conduction analgesia for labor, delivery, or cesarean section without the above hazard. The great concept is that by adding smaller amounts of both narcotic and local anesthetics, the benefits of both can be gained while the undesirable side effects of each are minimized.

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SPECIFIC MEDICATION Morphine Morphine (Duramorph), because of its relatively high water solubility, enjoys the advantage of having the longest duration of all the spinal opioids. It has been given in intrathecal doses from 0.1to1.0 mg. Common epidural doses range from 2 to 10 mg, although 5 mg is the most common. Phan et al. 49 demonstrated that varying the volume 5 ml or 10 ml for a given amount of epidural morphine made no difference with respect to duration, quality of analgesia, or side effects. They concluded that these variables are dependent solely on the mass of the drug given. Others have found no correlation between dosage and height and weight. Spinal opioids as a rule have proved to be of significant benefit for labor during the first stage. Abboud, Shnidedr et al. 5 demonstrated the effectiveness of 0.5 to 1.5 mg of intrathecal morphine for this purpose. High CSF levels of morphine may be obtained with doses as small as 0.25 mg. Obstetric patients reported that they could still "feel" their contractions, but were satisfied with their analgesia. Opioids alone have generally proved insufficient for analgesia during the second stage oflabor, and for instrumental vaginal deliveries, unless combined with local narcotics. The onset of analgesia with intrathecal morphine is similar to that of the epidural administration: 30 to 45 minutes. Furthermore, the side effects are just as prevalent. Behar11 was first to report the use of epidural narcotics (using Duramorph) for analgesia. Initial reports of epidural duramorph for labor analgesia were encouraging, but subsequent reports have proved less so. The general consensus is that 2.0 to 5.0 mg of meperidine (30-100 mg) when given epidurally for analgesia during the first stage oflabor tend to be inadequate, despite the contrasting success with intrathecal morphine. This is thought to be a result of the increased vascularity of the epidural space, which increases the vascular reuptake into the systemic circulation. Intrathecal administration suffers from the drawback of single shot application. Baraka10 overcame this by placing an epidural catheter in the spinal space for future local anesthetic administration for second stage and delivery analgesia. (The notion that placement of such a catheter would significantly increase the risk of spinal headache has now been seriously challenged.). Happily the application of spinal morphine (1 mg), or meperidine, although capable of providing analgesia, has not demonstrated a retarding effect on cervical dilation. However, Baraka observed that when doses of 2 mg of morphine were given intrathecally, an increase in oxytocin infusion was required in 61 per cent of the patients. This allows intraspinal narcotic techniques to be instigated early in labor at the first indication of pain, while it is yet relatively easy for the parturient to hold still. They then could be maintained throughout labor, to be supplemented by local anesthetics (most likely bupivacaine) in lower doses than otherwise would be necessary. This would offer the benefits of a reduction in cumulative amount oflocal anesthetic needed, and would also minimize the drop in SVR, which would otherwise be a consequence oflarger doses, in patients whose cardiac status dictates that afterload be preserved. Some investigators have attempted to provide quick-onset analgesia oflong duration by administering combinations of fentanyl with morphine. In an abstract Leighton et al. 38 studied nine parturients in whom 25 µg of fentanyl was combined with 0.25 mg ofDuramorph, diluted to a final volume of 2 ml, given intrathecally. They found, as expected, a brief latency period and satisfactory analgesia for 126 ± 58 minutes before requesting additional analgesia from local anesthetics epidurally. The side effects of itching, nausea, and headache were

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observed but mild in intensity. Respiratory rates were consistently above 16 per minute for 24 hours. The analgesia was profound, and no significant alterations in vital signs were seen. Morphine also has been combined with fentanyl (2 mg with 100 µg, respectively) for analgesia in a severely preeclamptic patient. Vincenti 66 reported that the narcotic analgesia succeeded in quickly reducing the blood pressure from 205/130 to 160/110. After the initial dose was administered, subsequent doses of epidural fentanyl, 100 µg in 6 ml of NS, were given as needed to maintain analgesia and control her blood pressure. The duration of analgesia, as judged by the redosing intervals, ranged from 2 to 3 hours. Blood pressure was kept steadily at 160 to 150/110to100 mm Hg. Her labor lasted for 12.5 hours, and she delivered an infant with 1- and 5-minute Apgar scores of 6 and 10, respectively. They concluded that the antihypertensive effect could be "ascribed to a strong direct action on spinal opiate receptors." The sedative effect was due to plasma levels of morphine acting on central receptors; this aspect was reversed with 0.4 mg of intravenous naloxone, but the antihypertensive effect was not, thus supporting the above conclusion. In 1983 El-Baz 26 reported the reduction in the side effects of duramorph when it was given as an infusion at 100 to 300 µg per hr. The postoperative analgesia was reported as satisfactory in 65 to 70 per cent of patients. However, fewer of the younger patients (age 50 years) were as satisfied; it was the older patients in whom the analgesia was greatest. This correlates with the fact that dose requirements for both narcotics and local anesthetics are decreased with increasing patient age. This abstract raises the interesting concept of replacing single duramorph doses with one initial bolus dose followed by continuous infusion, at adjustable rates for postoperative analgesia. Doses greater than those used in the above study would probably be required in the younger age groups. Morphine has been used to provide labor analgesia in a young woman with primary pulmonary hypertension. In 1983 Abboud3 reported the administration of 1 mg of Duramorph intrathecally to a 34-year-old G6 P5 parturient at 38 weeks' gestation who was admitted for hemoptysis, dyspnea and orthopnea. Her initial PA pressures were 111/38 mm Hg, with a near PA pressure of 64 mm Hg. Her room air blood gas values were Ph of 7.48, P0 2 of 50 mm Hg, and PC0 2 of 26 mm Hg. After 6 days of medical therapy (digoxin diuretics and potassium supplements) her labor began spontaneously. At 4 cm she became uncomfortable and the Duramorph was given as described. The onset of analgesic began just after 15 minutes. No changes in cardiac output or PAP nor systemic BP were noted. No respiratory depression was observed, and there were no changes in uterine activity or fetal heart rate. Mild pruritis was the only apparent side effect during labor. A pudenda! block with 15 ml of 1 per cent lidocaine was used for analgesia for the second stage of labor. She delivered 2 hours after the administration of the intrathecal morphine (Apgar scores 9 and 9 at 1 and 5 minutes). Epinephrine The controversy concerning whether epinephrine should be added to patients with hypertension, including preeclampsia, still rages. Bromage 14 showed, in 1983, that when epinephrine 1: 200,000 (5 µg per cc) was added to 10 mg of Duramorph (in an epidural injection of a total volume of 10 ml) and then compared to plain Duramorph of equal volumes, the addition of epinephrine caused a shortening of onset, a longer duration, and a more intense block. He also reported that the common side effects were also more intense, and the degree of respiratory depression was greater. He cited an earlier study that showed that epinephrine reduced the vascular absorbtion oflocal anesthetic by 60 per cent. He allowed that some of the effects were due to the direct analgesic action of epinephrine (as with norepinephrine and clonidine) on the alpha receptors in the spinal cord), but that these effects of direct interaction with the alpha receptors

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were too short lived to account for the analgesia and side effects, which were much longer in duration. They concluded that the severity of the side effects would prove unacceptable, but in reduced doses the results would be milder and better tolerated. Plasma concentrations of plain morphine after epidural administration are the same as when a similar dose is given subcutaneously. Therefore it has to be assumed the significant vascular uptake of epidural agents, including epinephrine, will occur. For example, plasma levels of 4 µg per ml oflidocaine have been measured when over 400 mg was placed in the epidural space. This plasma level was felt to be the cause of mild depression of myocardial contractility. Similar concerns have been voiced that systemic absorption of epinephrine might exacerbate existing hypertension and compromise uterine blood flow or the progress oflabor. In 1981 Albright and Touppila7 measured placental intervillous blood flow (using 133Xe) before and 15 to 20 minutes after 2 chloroprocaine, 10 ml, with 10 µg per ml of epinephrine added. They found no significant changes in intervillous blood flow, and postulated that despite the decrease in MAP from 94 to 83 mm Hg uteroplacental blood flow was preserved because of vasodilatation of the uterine vascular bed. They postulated that the decrease in placental vascular resistance may have been due to the beta2 -adrenergic-mediated vasodilatation resulting from the systemic absorbtion of epinephrine. Epidural analgesia's consequential reduction in catecholamine levels may also lessen the a-adrenergic vasoconstriction. They concluded that epidural epinephrine, in amounts of 40 to 100 µg, has no deleterious effect so long as significant hypotension is avoided. Abboud1 found that the addition of epinephrine 1: 300,000, to lidocaine or bupivacaine, prolongs the duration oflabor (186 vs 85 min. for bupivacaine, 106 vs 62 min. for lidocaine) and was associated with less maternal hypotension after instigation of the block but did not interfere with uterine activity or the progress of labor. The degree of satisfaction with the resulting analgesia was not statistically different between the epinephrine versus the nonepinephrine control groups. The latency periods were comparable as well. Generally speaking, when examining the cardiovascular differences when epinephrine is added to epidural local anesthetics in amounts sufficient to produce a T3- T 4 level of anesthesia, one sees an increase in heart rate, stroke volume, and therefore cardiac output when epinephrine is added, due to its inotropic and chronotropic beta1-adrenergic effects. It's a-stimulating properties are outweighed by its beta2-adrenergic properties, and a larger fall in SVR is seen over the nonepinephrine controls. These providential results are predicated on the assumptions that the epinephrine-containing local anesthetic is not accidentally injected intravenously, and that there is no preexisting cardiovascular disease. In a 1983 abstract, Hood et al. 31 reported the effects in ewes of the intravenous injection of epinephrine in doses of 5, 10, or 20 µg, in 5 mg of bupivacaine. Data were recorded for 15 minutes pre- and postinjection. Although the dose of plain bupivacaine failed to alter uterine blood flow (UBF), epinephrine did cause decrease of up to 58 per cent of control with 20 µg. Reductions in UBF were surprisingly not proportional to the dose of epinephrine injected. In the healthy animal models, these reductions in UBF (which became manifest within 30 seconds after injection and lasted up to 3 minutes) were not associated with significant fetal effects. These doses were chosen to approximate the amount which would be injected with a test dose in the labor setting. Mild increases in maternal blood pressure (101-112) and decreases in heart rate (128-116) were noted. Heller 29 and Goodman published a report in which women with varying degrees of preeclampia were given epidural local anesthetics containing epinephrine, 1: 400,000 or 1: 200,000. They found no significant increases in ma-

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ternal blood pressure, although one of the four patients did have an increase in heart rate from 85 to 130 beats per minute and a decrease in blood pressure (130/90 mm Hg to 100/60) after the institution oflumbar analgesia. They concluded that even when given in large amounts (130 µg), the slow vascular uptake of epinephrine from the vascular space allowed only for the beta-agonistic effects to become manifest. They pointed out earlier work that documented that epinephrine containing epidural anesthetics were associated with greater reductions in SVR and mean arterial blood pressure (MAP), with increased cardiac outputs and saw no reason why the preeclamptic should behave any differently in this regard. They cautioned and conceded that the hypertension that would result from an unintentional intravascular injection oflocal anesthetic containing epinephrine could be far more devastating in the preeclamptic patient. Dror and Abboud24 compared the hemodynamic consequences of epinephrine l : 200,000 in 8 ml of 1.5 per cent lidocaine for labor analgesia. Other than the prolongation of the local anesthetic block, there were no other differences between the epinephrine containing group and the control (plain 1.5 per cent lidocaine). Significant decreases in maternal blood flow were noted after the establishment oflumbar analgesia, and neonatal Apgar scores were good in both groups. They concluded that as long as the small, incremental doses of local anesthetics with epinephrine were employed, with the usual precautions against intravenous injection, that preeclamptic patients were unlikley to experience an exacerbation of their hypertension from the epidural epinephrine. In summary, numerous reports have documented the advantages of adding epinephrine to the various drugs used for epidural analgesia and anesthesia. Epinephrine prolongs the duration ofbupivacaine and Hdocaine in both intrathecal and epidural routes of administration. It may enhance the analgesia and its duration for Duramorph, although the side effects may also be exacerbated when higher doses (10 mg) are employed. Parker, Brookshire et al. 48 published a report of 21 patients given either fentanyl, sufentanil, or hydromorphine (Dilaudid) for postoperative analgesia, in doses equipotent to l 0 mg of Duramorph. They found that the addition of epinephrine did not prolong the duration of analgesia but in some patients increased the incidence of side effects. When the parturient has cardiovascular disease and hemodynamic instability, the consequences of an accidental intravenous injection of epinephrine-containing solutions are potentially disastrous. Furthermore, in the patient with such cardiac disease in whom an increase in heart rate, stroke volume, and therefore myocardial contractility and oxygen demand would be detrimental (such as coronary artery disease, IHSS, mitral or aortic stenosis), even the otherwise benign beta effects of epinephrine would be undesirable. In the same vein, the decreased SVR as a consequence of the beta2-adrenergic stimulation would be counterproductive in the various lesions outlined in the earlier section on cardiac disease. Therefore, despite its many proported advantages, epinephrine is probably best avoided in patients with cardiac disease, and its use in severe preeclamptic patients, the findings of the recent research not withstanding, is at best risky and controversial still, and definitely not for inexperienced hands. Better Mousetraps In this decade it has become apparent that the administration of spinal opioids for analgesia, or anesthesia when combined with local anesthetics for surgical purposes, has opened up an entirely new field of promise for those with the understanding and imagination to persevere. Taking advantage of the synergism that exists between narcotics and local anesthetic combinations of the two have reduced the total amount required of each, and as the total mass of each drug decreases, so do its side effects. The goal understandably then has been to offer profound and controllable analgesia and anesthesia with minimal side ef-

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fects. Morphine has been the standard against which all newcomers are measured. In the last six years various narcotics with or without local anesthetics, as isolated bolus doses or as infusion, with or without epinephrine, and at various pHs have been tried. The overall prevailing principle is that spinal opioids, like systemic opioids, have very little cardiovascular effects: myocardial contractility is unaltered, preload is preserved, and perhaps most importantly, SVR is not diminished. Their two limitations have been their inability to provide complete surgical anesthesia when administered alone (although intrathecal meperidine in doses of 1 mg per kg has been reported to achieve anesthesia, being postulated that it acts on the sodium channels in the manner of the local anesthetics, as well as the conventional receptor site) and the occurrence of side effects, particularly respiratory depression, which, in patients with preexisting pulmonary disease or advanced age, may be life threatening. Morphine's advantages are its potency and its duration, which, for the postoperative patient in whom analgesia is desired for several days to facilitate early ambulation, lends itself to a daily through the epidural catheter administration. Morphine's disadvantages are its prolonged latency period (sometimes > 45 minutes) and the potential for delayed respiratory depression 12 to 18 hours after administration. In a series of 1000 postoperative patients given 5 mg of Duramorph, Leight36 found the overall incidence of serious respiratory depression to be as low as 0.1 per cent. Researchers therefore have strived to find a means of obtaining quicker analgesia with fewer side effects. The following adventurous administrations were done for healthy parturients; however, the concepts so engendered have merit when applied to the patient with cardiovascular disease. Labor Analgesia As pointed out previously, intrathecal but not epidural morphine has proved to be effective for analgesia during the latent phase oflabor. Its principal drawback, besides the well-known side effects, is its prolonged latency period, which may rend it inappropriate in the labor setting. To this end, fentanyl, whose latency period is under 10 minutes, has been employed epidurally in combination with various other agents oflonger duration. Fentanyl, like the other phenylpiperidine derivatives, is quite lipophilic, enjoys a high degree of opioid receptor affinity, and does not migrate rostrally in the CSF as does morphine, therefore its incidence of side effects is low. Its chief drawback is its limited duration (2-5 hr). In 1985, Skerman58 reported on the addition of fentanyl to 0.25 per cent bupivacaine for labor analgesia in healthy parturients. The block was initiated with 0.25 per cent bupivacaine combined with 5 µg of fentanyl (in a volume appropriate for the individual's height) to establish an analgesic level ofTlO. An epidural infusion of both agents was then started at a rate of 1Occ per hour. Compared to the control ofbupivacaine alone, the fentanyl group had superior analgesia, with no significant changes in labor patterns nor fetal depression. In 1986, Cohen 18 looked at varying the amount of fentanyl with epidural bupivacaine 0.25 per cent for labor analgesia. They found that the optional combination was 50 µg of fentanyl added to 9 ml of 0.25 per cent bupivacaine. Intense analgesia oflonger duration (llO minutes, was obtained with a 30 per cent incidence of pruritis and excellent neonatal results. They observed the benefit of shorter first stages oflabor with the fentanyl group when compared to the bupivacaine alone controls. They speculated that this was the consequence of even greater reduction in plasma catecholamine levels, therefore achieving minimal interference with uterine activity. In an interesting abstract in 198 7 Grice et al. 28 reported that in 100 laboring patients who were receiving epidural doses of 0.25 per cent bupivacaine with 5 µg per ml of fentanyl, that the addition of epinephrine 3.75 µg per ml

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(1: 300,000) shortened the latency and increased the duration of analgesia between bolus doses. Butorphanol, a mu-receptor antagonist and a kappa-receptor agonist, has been added to both epidural morphine and fentanyl. Naulty 46 added doses of 1,2, or 3 mg ofbutorphanol (Stadol) to 10 ml of 0.25 per cent bupivacaine for labor analgesia. He found that the higher doses of Stadol reduced the total dose of bupivacaine employed by about 50 per cent and therefore decreased the degree of motor block concomitantly. The only side effect attributable to the stadol was moderate somnolence. The following year he looked at the effect of adding similar doses of Stadol to 50 µg of fentanyl for postcesarean analgesia. He found that stadol predictably lengthened the duration of fentanyl' s analgesia to around 250 to 350 minutes. He speculated that at low doses, mu antagonism reversed the analgesia related to fentanyl, and at higher doses, Stadol' s kappa agonism restored analgesia. No side effects of fentanyl were noted, and the somnolence noticed in the previous study was not seen. Synergism between the two produced greater analgesia than when 3 mg ofStadol was administered alone. Rein et al. 54 documented the existence of respiratory depression, as evidenced by elevated PC0 2 s at 2 and 4 mg of epidural Stadol, the larger dose prolonging the depression's duration, but only to the same degree of severity. In 1982 Baraka9 looked at meperidine's analgesic potentials. He found that when 100 mg of meperidine was given epidurally for labor analgesia, the ensuing analgesia was of faster onset, longer duration (161 versus 103 minutes) and of a higher percentage of satisfaction (12of13 versus 6of13) than for the control group of 10 ml of 0.25 per cent bupivacaine. He advised that because of its significant systemic aborption, it would be inadvisable to follow the initial doses with repeated doses, but to switch to a local anesthetic for maintenance of analgesia. He did note that subsequent doses ofbupivacaine were less frequent in the Demerol group. Sufentanil has an ever greater affinity for the mu receptor than fentanyl. It generally will produce analgesia in 5 to 45 minutes with a duration of 1.5 to 6 hours, when given in doses of7.5 to 75mg.In1987 Phillips50 reported the use of sufentanil in 10, 20, and 30 µg doses combined with 0.25 per cent bupivacaine. He found that with sufentanil, the onset of analgesia was quicker (less than 10 minutes) and of longer duration (144 minutes) which was longer than that reported by an earlier group for 50 µg of fentanyl (108 min). Of interest, there was no significant improvement in the quality of analgesia when compared to the 0.25 per cent bupivacaine control group. They speculated that, as was true for fentanyl combined with 0.125 per cent bupivacaine, the addition of sufentanil to lower concentrations oflocal anesthetic would significantly improve the quality of analgesia over that achieved by local anesthetics alone. Van de Auwera64 reported a smaller decrease in MAP (8 per cent) when contrasted to that associated with morphine (15 per cent). Klepper35 found that the addition of epinephrine (1: 200,000) prolonged the duration of analgesia produced by 50 mg of sufentanil (4.5-5.5 hours vs 1.5-3.5 hours). Intraoperative Anesthesia For surgical anesthesia, most studies have looked at various combinations of narcotics with local anesthetics for subarochnoid block. In 1988, Aboulish 6 reported the addition of 0. 2 mg of morphine to 0. 7 5 per cent bupivacaine for spinal anesthesia. Knowing that higher doses (1.0 mg) of spinal morphine were associated with high incidences of side effects, he sought to discover the efficacy of lower doses of morphine with hopefully fewer side effects as well. The quality and duration of intra- and postoperative analgesia was improved, and no respiratory depression was observed. Nausea and itching were treated with naloxone. N aulty 11 investigated various doses of fentanyl added to 0. 7 5 per cent bupiva-

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caine, and found that as little as 6.25 µg (1/8 of a ml) improved the quality and duration of analgesia. Larger doses (up to 50 µg) only increased the incidence of side effects. Preston et al. 51 found that when epidural fentanyl in doses of 1 µg per kg was added to 2 per cent lidocaine with 1: 200,000 epinephrine that intra- and postoperative analgesia was improved without adverse consequences to either mother or neonate. Stormiol62 found that the addition of 35 mg of meperidine to 0.5 per cent carbonated bupivacaine with epinephrine 1: 200,000 reduced the incidence of postoperative shivering, which would be of consequence in patients with cardiac compromise. Postoperative Analgesia Morphine has always been the "gold standard" for postoperative analgesia, in doses ranging from 3 to 10 mg. Its analgesia can last for as long as 27 hours. Rau ck et al. 52 compared epidural Duramorph given as a bolus of 0. 2 7 mg per kg at the close of surgery versus a bolus of 0 .03 mg per kg followed by an infusion of 0.5 mg per hour (at a rate of 5 ml per hr). The infusion was titrated to effect and doses ranged from 0.2 to 1 mg per hour. Overall patient satisfaction was better in the infusion group, and there were no adverse effects, suggesting that an infusion ofDuramorph would be a clinically superior method of administration for postoperative analgesia. Hjortso 30 found superior postoperative analgesia when morphine was added to a bupivacaine infusion (0.5 mg of morphine plus 0.5 per cent ofbupivacaine in 8 ml per hr). Naulty 47 added1,2, or 3 mg of morphine to epidural fentanyl (50 µg), diluted to a total volume of 10 ml, given through the epidural catheter. When contrasted to 5 mg of duramorph alone, he found the optimal dose of morphine was 3 mg. This gave fewer side effects (primarily pruritis) and longlasting analgesia (16 hr or more). The conclusion then was that the combination of 3mg of duramorph with 50 µg of fentanyl provided the best of both worlds: fentanyl's short onset with Duramorph's long duration at a minimal cost of side effects. Because the more lipid soluble narcotics are associated with fewer side effects, fentanyl alone, given as an infusion, has been examined by various investigators. In 1985, Rollin 55 used a loading dose of 100 µgin 8 ml of NS, followed by a continuous infusion of 5 µg per cc of fentanyl at a rate ranging from 10 to 35 ml per hour (50-157 µg of fentanyl/hour) according to patient need. Their additional concern was to investigate whether pressures in the epidural space would rise, in response to the volume load, to a dangerous degree. They found this not to be true. Bell 12 found good postoperative analgesia when, after a loading dose of 50mcg of fentanyl, repeated in 20 minutes if needed, an infusion of fentanyl ranging from 80 to 130 µg per hr. was administered. His patients were in the surgical ICU after repair of an abdominal aneurysm. He found that the analgesia provided allowed for better compliance with pulmonary toilet, and the adjustment of the infusion rate to be relatively simple due to fentanyl's rapid onset of action. An interesting study was published by Arcario 8 in1987, in which he varied the volume of normal saline (NS) into which 50 µg of fentanyl was administered epidurally. Interestingly he found the duration to be longest, and the onset to be quicker, in volumes greater than 20 ml. In 198 7 Cheng 1 7 used sufentanil in a similar manner and setting. He obtained good pain relief with minimal side effects utilizing a loading dose of O. 3 µg per kg in 8 ml of NS, followed by a repeat bolus if pain was still reported after 10 minutes. An infusion of 0.3 µg per kg per hour of sufentanil in a volume of 8 ml per hour was begun. Johnson34 found optimal postoperative analgesia with 50 to 7 5 mg of epidural sufentanil with the added benefit of reduction in postoperative shivering without the risk of significant hypothermia. Leight 37 measured the duration of analgesia following 60 µg of epidural sufentanil and found it to be an

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average of 338 minutes (255He believed the effects of sufentanil to be noncumulative and that acute tolerance does not occur. Rosen 56 et al. compared doses of 30, 45, and 60 µg of sufentanil to 5 mg of They were disappointed in the short durations of analgesia. When given in doses of 60 µg, the duration was 5.6 hours. The quality was equivalent to that achieved by duramorph. They noted the duration to be similar to that provided by epidural fentanyl. They noted a similar incidence of side effects, save a reduction in pruritis (1 7 vs 15 per cent for sufentanil). They saw the optimal use of sufentanil as being that of infusion, or in small repeated doses, since accumulation does not occur. They also speculated that it might be beneficial to combine it with duramorph for epidural analgesia. This calls to mind the question of whether there would be any real advantage of sufentanil over fentanyl in this setting. CONCLUSION In summary, humanity's quest for relief from pain goes on. With the advent of spinal opioids, a new and exciting chapter is now being penned by researchers whose only limit is their own imagination. Great promise lies ahead as more of the secrets of the multiple endogenous analgesia systems of the central nervous system are elucidated, and more selective analgesia compounds are synthesized. The degree of selectivity for analgesia only is ever more closely approaching the asymptote of purity of affect, thus allowing clinicians to offer treatment and hope to cardiac patients for whom little existed formerly. Certainly the trend would seem to be towards the infusion of one or more analgesics whose effects are easily titratable to precisely match the analgesic need of the individual patient. Patient controlled analgesia (PCA) has been investigated in the self-administration of intravenous analgesics. Perhaps this concept will one day be applicable to intrathecal and epidural opioid administration as well. As ever we advance in the spectrum of our treatments, our enemy paces yet further ahead in scope and destruction, so we are forced to ask ourselves as physician the question put by Shakespeare's Macbeth to his wife's physician: Canst thou not minister to a mind diseased, Pluck from the memory a rooted sorrow, Raze out the written troubles of the brain, And with some sweet oblivious antidote Cleanse the stuffed bosom of that perilous stuff Which weighs upon the heart? Doctor: Therein the patient must minister to himself.

REFERENCES l. Abboud TK, Amir Sheik-ol-Eslam et al: Safety and efficacy of epinephrine added to bupivacaine for lumbar analgesia in obstetrics. Anesth Analg 69:585-591, 1985 2. Abboud TK, Dror A, Mosaad P: Mini-dose intrathecal morphine for the relief of postcesarean section pain: Safety, effiacy and ventilatory responses to C0 2 . SOAP Abstract, 1986 3. Abboud TK, Raya J, et al: Intrathecal morphine for relief of labor pain in a parturient with severe pulmonary hypertension. Anesthesiology 59:477-479, 1983 4. Abboud TK, Sheikh-ol-Eslam, Yanagi T et al: Safety and efficacy of bupivacaine for lumbar epidural analgesia in the parturient. ASA Abstract, V61, A406, 1984 5. Abboud TK, Shnider SM, Dailey PA et al: Intrathecal administration of hyperbasic morphine for the relief of pain in labor. Br J Anaesth 56:1351-1360, 1984 6. Abouleish E, Rawal N, Fallon Ket al: Combined intrathecal morphine and bupivacaine for cesarean section. Anesth Analg 67:370-374, 1988

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7. Albright ZA, Jouppila et al: Epinephrine does not alter human intervillous blood flow during epidural anesthesia. Anesthesiology 54:131-135, 1981 8. Arcario T, Vartikar T, Johnson et al: Effect of diluent volume analgesia produced by epidural fentanyl. Anesthesiology 67:A441, 1987 9. Baraka A, Maktabi M, Noveihid R: Epidural myperidine-bupivacaine for obstetric analgesia. Anesth Analg 61:65206, 1982 10. Baraka A, Noueihid R, Hajj S: lntrathecal injection of morphine for obstetric analgesia. Anesthesiology 54:136-140, 1981 11. Behar M, Magora Fetal: Epidural morphine in treatment of pain. Lancet 1 :527 -528, 1979 12. Bell SD, Levette A, Larijani GE: The use of continuous lumbar epidural fentanyl for Postoperative Pain Relief in Abdominal Aortic Aneurysms, ASA Abstracts Anesthesiology V67 No 3A A234, 1987 13. Booker PD, Wilkes RZ et al: Obstetri pain relief using epidural morphine. Anesthesia 35:377-379, 1980 14. Bromage, Camporesi E, Durant Pet al: Influence of epinephrine as an adjurant to epidural morphine. Anesthesiology 38:257-262, 1983 15. Chernow B, Holbrook Pet al: Epinephrine absorbtion after intrathecal administration. Anesth Analg 63:829-832, 1984 16. Chester WL, Shubert A et al: Intrathecal morphine: Perioperative effects. Anesthesiology 67:(3A)A267, 1987 17. Cheng Y, Koebert RF et al: Continuous epidural sufentanil infusion for post-operative analgesia. Anesthesiology 67:A233, 1987 18. Cohen SE, Tan S, Albright GA et al: Epidural fentanylfbupivacaine combinations for labor analgesia: Effect of varying doses. ASA Abstracts Anesthesiology 65:A368, 1988 19. Coriat P, Benammar MS et al: Lumbar epidural anesthesia improves ejection fraction in patients with poor left ventricular function. Anesthesiology 67:A259, 1987 20. Cousins MJ, Mather LE (letter to the editor): Selective spinal analgesia. Lancet 1:1141-1142, 1979 21. Cousins MJ, Bridenbaugh PO: Neural blockade in clinical anesthesia and management of pain. Philadelphia, JB Lippencott, 1988, pp 806-808; 983-1001 22. Cousins MJ, Mather LE: lntrathecal and epidural administration of opioids. Anesthesiology 61:276-310, 1984 23. Douglas MJ, McMorland ZH: The effect of pH adjustment ofbupivacaine on epidural anesthesia for cesarean section. ASA Abstracts. Anesthesiology 65:A380, 1986 24. Dror A, Abboud TK et al: Maternal hemodynamic responses to epinephrine containing local anesthetics on pre-eclampsia. SOAP Abstract, 1987 25. Eisenach JC, Grice SC, Dewan DM: Effect of epinephrine on the duration of analgesia with bupivacaine. Anesthesiology, 65:A376, 1986 26. El-Baz NM, El-Ganzouri A et al: Continuous epidural morphine infusion with postoperative pain relief. Anesth Analg 62:258, 1983 27. Grice SC, Eisenach JC et al: Effect of epinephrine on the duration of analgesia with epidural bupivacaine and fentanyl. ASA Abstracts. Anesthesiology 67:A440, 1987 28. Grice SC, Eisenach JC et al: Effect of fentanyl and epinephrine on the duration of analgesia with epidural bupivacaine. SOAP Abstract, 1987 29. Heller PJ, Goodman C: Use oflocal anesthetics with epinephrine for epidural anesthesia in preeclampsia. Anesthesiology 65:224-226, 1986 30. Hjortso NC, Lund C et al: Epidural morphine improves pain relief and maintain sensory analgesia during continuous epidural bupivacaine after abdominal surgery. Anesth Anagl 65:1033-6, 1986 31. Hood DD, Dewan DM et al: Maternal and fetal effects of intravenous epinephrine containing solutions in gravid ewes. Anesthesiology 59:A393, 1983 32. Hughes SC, Shnider S, Levinson D: lntraspinal opiates in obstetrics. In Anesthesia for Obstetrics, Ed 2. Baltimore, MD, Williams & Wilkins, 1987, pp 123-139 33. Hunt CO, Datta S et al: Preoperative analgesia with subarachnoid fentanyl-bupivacaine. SOAP Abstract, 1985 34. Johnson MD, Sevarino FB, N aulty JS et al: Effect of epidural sufentanil on temperature regulation in the parturient. ASA Abstracts. Anesthesiology 67:A450, 1987 35. Klepper ID, Sherrill DL et al: Analgesia and respiratory effects of extradural sufentanil

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in volunteers and the influence of adrenaline as an Br J Anaesth 59: 1147-1156, 1987 Leicht CH, Hughes SC, Dailey PA et al: Epidural morphine sulfate for analgesia after cesarean section: A prospective report of 1000 patients. ASA Abstracts. Anesthesiology 65:A366, 1986 Leicht CH, Rosen MA, Dailey PA et al: Evaluation and comparison of epidural sufentanil citrate and morphine sulfate for analgesia after cesarean section. Anesthesiology 65:1986 Leighton BL, DeSimone CA et al: Subarachnoid narcotics for labor revisited: Fentanyl 25 mcg and morphine 0.25 mg provide rapid, profound anaglesia. SOAP Abstract, 1984 Little MS, McNitt JD et al: A pilot study of low-dose epidural sufentanil and bupivacaine for labor anesthesia. ASA Abstracts. Anesthesiology 67:A444, 1987 Mangano DT, Shnider S, Levinson D: Anesthesia for the pregnant cardiac patient in anesthesia for obstetrics, Ed 2. Baltimore, MD, Williams & Wilkins 1987, pp 345372 Martin R, Lamarche Y et al: Epidural and Intrathecal Narcotics. Can Anesth Soc J 30:662-673, 1983 Minnich ME, Quirk JG, Clarke PB: Epidural anesthesia for vaginal delivery in a patient with IHSS. SOAP Abstract, 1985 Mircea N: Anesthesie sous-arachnoidienne par la Pethidine. Ann Fr Anesth Reanim 1:167-171, 1982 Naulty JS, LaBoue Pet al: Epidural butorphanol/fentanyl for postcesarean delivery analgesia. Anesthesiology 67:A463, 1987 Naulty JS, Malinow A, Hunt CO et al: Epidural butorphanol for analgesia during labor and delivery. SOAP Scientific Exhibit, SOAP 1985 Naulty JS, Malinow A, Hunt Co et al: Epidural butorphanol-bupivacaine for analgesia during labor and delivery. Anesthesiology 65:A369, 1986 N aulty JS, Ross R: Epidural fentanyl and morphine for postcesearean delivery analgesia. SOAP Abstract, 1986 Parker EO, Brookshire GL: Effects of epinephrine on epidural fentanyl, sufentanil and hydromorphone for postoperative analgesia. Anesthesiology 63: No 3A A235, 1985 Phan CQ, Azor Fetal: The quality epidural morphine analgesia following cesarean delivery as affected by the volume of the injectant anesthesiology. 67:A285, 1987 Phillips CH: Epidural sufentanil/bupivacaine combinations for analgesia during labor: Effect of varying sufentanil doses. Anesthesiology 67:835-838, 1987 Preston P, Rosen M, Shnider S et al: Epidural fentanyl with lidocaine for cesarean section. ASA Abstracts. Anesthesiology 67:A442, 1987 Rauck R, Knarr D et al: Comparison of the efficacy of epidural morphine given by intermittent injection or continuous infusion for management of postoperative pain. Anesthesiology 65:A201, 1986 Raggi R, Dardik H et al: Continuous epidural anesthesia and postoperative epidural narcotics in vascular surgery. Am J Surg 154:192-197, 1987 Rein P, Brothers W et al: Respiratory depressant effect of epidural butorphanol. Anesthesiology 63:A247, 1985 Rollin V, Oden MD et al: Epidural space pressures during continuous epidural fentanyl infusion. ASA Abstracts. Anesthesiology 63:3A, 1985 Rosen MA, Dailey PA, et al: Epidural Sufentanil for Postoperative Analgesia After Cesarean Section. Anesthesiology 68:448-454, 1988 Samii K, Chauvin M, Viars P: Postoperative spinal analgesia with morphine. Br J Anaesth 53:817-820, 1981 Skerman JH, Thompson BA et al: Combined continuous epidural fentanyl and bupivacaine in labor: A randomized study. ASA Abstracts. Anesthesiology 63:A450, 1985 Sorenson MB, Korshin JD et al: The use of epidural analgesia for delivery in a patient with pulmonary hypertension. Acta Anaesth Scand 26: 180-182, 1982 Spinnato JA, Krayrack BJ, Cooper MW: Eisenmanger's syndrome in pregnancy: Epidural anesthesia for elective cesarean section. N Engl J Med 304: No 20, 1981 Stoelting RK: Pharmacology and Physiology in Anesthetic Practice. Philadelphia, JB Lippincott, 1987, pp 69-92

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62. Stormiolo FR, Cheek TG, Gutsche BB: Maternal and neonatal effects of epidural meperidine and fentanyl during cesarean section. SOAP Abstract, 1986 63. Sullivan JM, Ramanathan KB: Management of medical problems in pregnancy-severe cardiac disease. N Engl J Med 313:No 5, 1985 64. Van der Auwera D, Verborgh C, Camu F: Analgesic and cardiorespiratory effects of epidural sufentanil and morphine in humans. Anesth Analg 66:999-1003, 1987 65. Van Steenberge A, Debroux HC, N oorduin H: Extradural Bupivacaine with Sufentanil for Vaginal Delivery. Br J Anaesth 59: 1518-1522, 1987 66. Vincent E: Epidural narcotics and control of arterial pressure in a pre-eclamptic patient. Can Anaesth Soc J: 405-406, 1986 6 7. Wang JK, Nauss LA, Thomas LE: Pain relief by intrathecally applied morphine in man. Anesthesiology 50:149-151, 1979 68. Wilkin OC, Blass NH, Ellis R: Epidural anesthesia and uterine contractions: Their effects on cardiac output. SOAP Abstract, 1987 69. Yaksh TL: Spinal opiate analgesia: Characteristics and principles of action. Pain 11:293-346, 1981 70. Yanagi T, David S, Abbout T et al: Maternal, fetal, and neonatal effects of lidocaine with and without epinephrine for epidural anesthesia in obstetrics. Anesth Analg 63:973-979, 1984 (Thomas Joyce III, MD) Department of Anesthesia 435D Baylor College of Medicine 1 Baylor Place Houston, TX 77030