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A dedication

First of all I dedicate this book to the great Allah who help me to do this work secondly I dedicate this work to my parents and to my women colleagues .and advise them to take broader steps as men colleagues in scientific working and help our communities grow up in all fields. I must thank Lambert publishing group to help me in spreading my work over the world.   



              ϭ 

Table of contents

A dedication

Author Advantages of spinal anesthesia

1

2 4

Basic concepts on spinal anesthesia

5

Mechanism of action of neuroaxial blockade

9

Contraindications of spinal anesthesia

11

Complications of spinal anaesthesia

13

Pharmacology of local anesthetics

19

Factors affecting intrathecal spread

22

Additives in itrathecal block

23

Pharmacology of additives

27

Serious side effect of intrathecal opioids

30

Nalbuphine as an additive in spinal anesthesia

32

References

35

Research on Intrathecal Nalbuphine .

44

Ϯ 

  

Spinal anesthesia, and opioid additives.

Hala M Goma MD, professor of anesthesia Faculty of medicine Cairo University

Corresponding

author Hala M Goma MD

[email protected]

Coauthor of Diagnostic Techniques and Surgical Management of Brain Tumors Copyright © 2011 InTech.

Coauthor of Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors Published April, 2013.

ϯ 

Advantages of spinal anesthesia:

Spinal anesthesia provides adequate anesthesia plus postoperative analgesia lead to reduction requirements of systemic opioids resulting in avoidance of sedation and respiratory depression. More importantly, the inhibition of the stress response to surgery, trauma induced nociceptive impulses, and blunting of the autonomic and somatic responses to pain facilitate breathing, coughing, sighing and early ambulation (1). This results in restoration of pulmonary function and reduction of post operative chest infection and pulmonary collapse. Finally, efferent sympathetic blockade results in increased blood flow to the region of neural blockade resulting in better wound healing and reduced risk of deep venous thrombosis and thromboembolism (2).

ϰ 

Basic concepts on spinal anesthesia I. Anatomical Considerations.

The vertebral column. The spine is composed of the vertebral bodies and fibrocartilaginous intervertebral disks. There are 7 cervical, 12 thoracic, and 5 lumbar vertebrae. The sacrum is a fusion of 5 sacral vertebrae, and there are small rudimentary coccygeal vertebrae. The spine as a whole provides structural support for the body and protection for the spinal cord and nerves, and allows a degree of mobility in several spatial planes. At each vertebral level, paired spinal nerves exit the central nervous system (3). The spinal canal contains the spinal cord with its coverings (the meninges), fatty tissue, and a venous plexus. The meninges are composed of three layers: the pia mater, the arachnoid mater, and the dura mater; all are contiguous with their cranial counterparts. The pia mater is closely adherent to the spinal cord, whereas the arachnoid mater is usually closely adherent to the thicker and denser dura mater (4). CSF is an isotonic, aqueous medium with a constitution similar to interstitial fluid. CSF is contained between the pia and arachnoid matters in the subarachnoid space (3). The spinal cord. The spinal cord normally extends from the foramen magnum to the level of L1 in adults. The anterior and posterior nerve roots at each spinal level join one another and exit the intervertebral foramina forming spinal nerves from C1 to S5. At the cervical level, the nerves arise above their respective vertebrae, but starting at T1 they exit below their vertebrae. Because the spinal cord normally ends at L1, lower nerve roots course some distance before exiting the intervertebral foramina. These lower spinal nerves form the cauda equina ("horse tail"). Therefore, performing a lumbar (subarachnoid) puncture below L1 in an adult avoids potential needle trauma to the cord; ϱ 

damage to the cauda equina is unlikely as these nerve roots float in the dural sac below L1 and tend to be pushed away (rather than pierced) by an advancing needle (4).

In the midline approach for spinal anesthesia the traversed anatomy layers are skin, subcutaneous fat, supraspinous ligament, interspinous ligament, ligamentum flavum, dura, subdural space, arachnoid, and finally the subarachnoid space. When the paramedian technique is applied, the spinal needle should traverse the skin, subcutaneous fat, ligamentum flavum, duramater, subdural space, arachnoid, and then pass into the subarachnoid space (3). The blood supply to the spinal cord and nerve roots is derived from a single anterior spinal artery and paired posterior spinal arteries. The anterior spinal artery is formed from the vertebral artery at the base of the skull and courses down along the anterior surface of the cord. The anterior spinal artery supplies the anterior two-thirds of the cord, whereas the two posterior spinal arteries supply the posterior one-third. The posterior spinal arteries arise from the posterior inferior cerebellar arteries and course down along the dorsal surface of the cord medial to the dorsal nerve roots (3). II. Physiological considerations are determined by the effects of interrupting the afferent and efferent innervations of somatic and visceral structures. Somatic structures are traditionally related with sensory and motor innervations, while the visceral structures are more related to the autonomic nervous system. Prevention of pain and skeletal muscle relaxation are classic objectives of central blockade. Nerve fibers are not homogenous. There are three main types of nerve fibers designated A, B and C. The A group has four sub-groups alpha, beta, gamma and delta. The minimum concentration of local anesthetic required to stop transmission (Cm) varies depending upon fiber size (5).

Class

Action

Myelin

Size

ϲ 



Motor

Yes

++++



Light touch, pressure pain

Yes

+++



Proprioception

Yes

+++



Pain, temperature

Yes

++

B

Preganglionic sympathetic fibers

Yes

++

C

Pain, pressure

No

+

(3).

Most of the visceral effects of central blockade are mediated by interruption of autonomic impulses to various organ systems. Sympathetic blockade results in cardiovascular changes of hemodynamic consequence in proportion to the degree of sympathectomy. The sympathetic chain originates from the lumbar and thoracic spinal cord. The fibres involved in smooth muscle tone of the arterial and venous circulation arise from T5 and L1. Arteries retain most of their tone despite sympathectomy because of local mediators and there is no arteriolar vasoplegia, but the venous circulation does not. The consequence of total sympathectomy is an increase in the volume of the capacitance vessels, specially in the splanchnic circulation, decreasing the venous return to the heart and hypotension occurs (6). The cardiac accelerator fibers are sympathetic efferents, which increase heart rate when stimulated. When blocked by high central l blockade, unopposed vagal action leads to bradycardia (4). Prophylactic administration of pharmacologic agents may be more effective than prehydration to prevent hypotension (7). Į-adrenergic agents (e.g., phenylephrine) reliably increase arterial blood pressure by increasing systemic vascular resistance, however, heart rate and cardiac output may decrease because of increased after load (8). Į- and ȕ- adrenergic agonists (e.g., ephedrine) are ϳ 

effective for increasing arterial blood pressure preventing hypotension but act by primarily increasing heart rate and cardiac output with a smaller increase in systemic vascular resistance (9). Initial treatment can be tailored to Į- agonists on patients with hypotension and mixed Į and ȕ agonist on patients with both hypotension and bradycardia (9) Clinically significant alterations in pulmonary physiology are usually minimal with neuroaxial blockade because the diaphragm is innervated by the phrenic nerve with fibers originating from C3-C5. Even with high levels, tidal volume is unchanged; there is only a decrease in vital capacity, which results from a loss of abdominal muscles' contribution to forced expiration (3). Patients with severe chronic lung disease may rely upon accessory muscles of respiration (intercostal and abdominal muscles) to actively inspire or exhale. High levels of neural blockade will impair these muscles. Similarly, effective coughing and clearing of secretions require these muscles for expiration. For these reasons, neuroaxial blocks should be used with caution in patients with limited respiratory reserve (4). Neuroaxial anesthesia at lumbar and sacral levels blocks both sympathetic and parasympathetic control of bladder function resulting in urinary retention until the block wears off (4).

ϴ 

Mechanism of action of neuroaxial blockade

Spinal nerve roots are the principal site of action for neuroaxial blockade. Local anesthetic is injected into CSF and bathes the nerve roots in the subarachnoid space. Direct injection of local anesthetic into CSF for spinal anesthesia allows a relatively small dose and volume of local anesthetic to achieve dense sensory and motor blockade. Blockade of neural transmission (conduction) in the posterior nerve root fibers interrupts somatic and visceral sensation, whereas blockade of anterior nerve root fibers prevents efferent motor and autonomic outflow (3). When preparing for spinal anesthetic blockade, it is important to find landmarks on the patient. The iliac crests usually mark the interspace between the fourth and fifth lumbar vertebrae, and a line can be drawn between them to help locate this interspace. Care must be taken to feel for the soft area between the spinous processes to locate the interspace. Depending on the level of anesthesia necessary for the surgery and the ability to feel for the interspace, the L3-4 interspace or the L4-5 interspace can be used to introduce the spinal needle. Because the spinal cord ends at the L1 to L2 level, it would not be wise to attempt spinal anesthesia at or above this level (10) A dermatome is an area of skin innervated by sensory fibers from a single spinal nerve. The tenth thoracic (T10) dermatome corresponds to the umbilicus, the sixth thoracic (T6) dermatome the xiphoid, and the fourth thoracic (T4) dermatome the nipples. To achieve surgical anesthesia for a given procedure, the extent of spinal anesthesia must reach a certain dermatomal level (11).

ϵ 

Figure 2. Dermatomes of the body (11).

ϭϬ 

Contraindications of spinal anesthesia: There are absolute and relative contraindications to spinal anesthesia. The only absolute contraindications include patient refusal, infection at the site of injection, hypovolemia, indeterminate neurologic disease, coagulopathy, and increased intracranial pressure, except in cases of pseudotumor cerebri. Relative contraindications include sepsis distinct from the anatomic site of puncture (e.g., chorioamnionitis or lower extremity infection) and unknown duration of surgery. In the latter case, if the patient is on antibiotics and the vital signs are stable, spinal anesthesia may be considered.

Absolute:



Infection at site of injection.



Patient refusal.



Coagulopathy or other bleeding diathesis.



Severe hypovolemia.



Increased intracranial pressure.



Severe aortic stenosis.



Severe mitral stenosis.

Relative:



Sepsis.



Uncooperative patient.



Preexixting neurological deficits.



Demyelinating lesions.



Stenotic valvular heart lesions.



Severe spinal deformity.

Controversial:



Prior back surgery at the site of injection.



Complicated surgery.

ϭϭ 



Prolonged operation.



Major blood loss.



Maneuvers that compromise respiration.

(3)

ϭϮ 

Complications of spinal anaeesthesia: Complications of spinal blockkade include local anesthetic neurotoxicity and neurologic injury, PDPH, high spinal blockade, and a cardiovascular collapse. Neurotoxicity sttudies performed in animal models producing neurrologic deficits and changes in spinal cord hisstology are not seen in clinically useful concentrationns of tetracaine, lidocaine, bupivacaine, or chlloroprocaine in humans. High concentration teetracaine and lidocaine causes histopathologic changes and neurologic deficits in animal models.[200-202] m Spinal cord blood flow is in ncreased, and vasodilation occurs with intratthecal bupivacaine, lidocaine, mepivacaine, aand tetracaine, but ropivacaine causes vasoconstrriction and decreased spinal blood flow in a dose-dependent d fashion. TNS may occur with spinal anesthesia, usually with lidocaine. Som me of the most bothersome and serious complications are:

Backache:Although postoperativve backache occurs after general anesthesia, it iss more common after epidural and spinal anesthesia. The T etiology of backache is not clear, although nneedle trauma, local irritation, and ligamentous strainn secondary to muscle relaxation have been offerred as explanations (12).

Post-dural puncture headache (P PDPH). PDPH is the most common complication of spinal anesthesia. It occurs most frequently in youngg adults including obstetric patients, with an incidence rate of 14%, compared to 7% in individuals older o than 70 years (12).Traditional concepts sug ggest that dural puncture causes leak of CSF with resultan nt loss of CSF causing gravitational traction of bbrain structures, and neurovascular response from thee meninges. Prompt treatment is essential and co onsists of providing adequate hydration (orally or inttravenously), and analgesics. A single oral dose of caffeine was demonstrated to be safe, effectivve and should be considered in the early treatmennt of mild PDPH (13). Cosyntropin, a synthetic form of adrenocorticotropic hormone, has been used inn the treatment of otropic hormone is believed to work by stimulatting the adrenal gland to refractory PDPH. Adrenocortico increase CSF production and ȕ--endorphin output (14). If conservative therapy fails, an epidural patch with 10-15ml of autologous bloood injected at the site of meningeal tear may be necessarry to minimize the leakage of CSF (15). Accidental dural puncture (AD DP) is a recognised complication of epidural aanaesthesia. Dural puncture with a 16-G Tuohy needle n can result in severe post-dural puncturee headache (PDPH) in ϭϯ 

up to 88% of cases (16,17). The incidence of severe PDPH is significantly higher following ADP with a 16-G needle rather than a 17- or 18-G needle (16). Neurologic complications: The most benign neurologic complication is aseptic meningitis. This syndrome usually presents within 24 hours of spinal anesthesia and is characterized by fever, nuchal rigidity and photophobia. Microscopic examination of CSF is characterized by polymorphonuclear leukocytosis. Bacterial CSF cultures are negative. Aseptic meningitis requires only symptomatic treatment and usually resolves within few days. Etiology of chemical meningitis was previouslyconsidered to be related to the cleansing agents and antiseptics adhering to syringes and needles used for spinal anesthesia (18).

Cauda equina syndrome may occure after regression of the neuroaxial blockade. An acute subdural hematoma may be the cause, and is believed to have resulted from direct vascular trauma during administration of spinal anesthesia or from vascular trauma combined with thrombocytopenia in the postoperative period. This syndrome may be permanent, or it may regress slowly over weeks or months. It is characterized by a sensory deficit in the perineal area, urinary and fecal incontinence, and varying degrees of motor deficit in the lower extremities (19).

The most serious neurological complication is adhesive arachnoiditis. This reaction usually occurs several weeks or even months after spinal anesthesia. The syndrome is characterized by a gradual progression of sensory deficits and motor weakness in the lower limbs. There is a reaction and vasoconstriction of the spinal cord vasculature.

Spinal cord ischemia and infarction may occur after prolonged periods of arterial hypotension. The use of epinephrine in anesthetic solutions may reduce blood flow to the spinal cord (20).

Adverse or exaggerated physiological responses:



Hypotension.



Bradycardia.



High block.



Total spinal anesthesia.

ϭϰ 



Cardiac arrest.



Urinary retention.



Anterior spinal artery syndrome.



Horner's syndrome.

Complications related to needle placement



Trauma.



Backache.



Postdural puncture headache.



Diplopia.



Tinnitus.



Neural injury.



Nerve root damage.



Spinal cord damage.



Cauda equina syndrome.



Bleeding.



Intraspinal hematoma.



No effect/inadequate anesthesia.



Inadvertent intravascular injection.



Inflammation.



Infection.



Meningitis.

Drug toxicity:



Systemic, or local anesthetic toxicity.



Transient neurological symptoms.



Cauda equina syndrome.

(3)

Urinary retention. As the sacral autonomic fibers are among the last to recover following a spinal anesthetic, urinary retention may occur (4).

ϭϱ 

Spinal hematoma. A clinically significant spinal hematoma can occur following spinal or epidural anesthesia, particularly presence of abnormal coagulation or bleeding disorder (5).When hematoma is suspected, neurological imaging (magnetic resonance imaging [MRI], computed tomography [CT], or myelography must be obtained immediately and neurosurgical consultation should be requested (11). In this book there is a chapter on spinal hematoma, which is recommended to read for more complete information.

Total spinal. Total spinal anesthesia occurs when local anesthetic spread is high enough to block the entire spinal cord and occasionally the brain stem. Profound hypotension and bradycardia are common secondary to complete sympathetic blockade. Respiratory arrests may occur as a result of respiratory muscle paralysis or dysfunction of brain stem respiratory control centers. Management includes vasopressors, atropine, and fluids as necessary to support the cardiovascular system plus oxygen and controlled ventilation. If the cardiovascular and respiratory consequences are managed appropriately, total spinal block will resolve without sequelae (11)

Failed neuraxial block. A failed neuraxial block may be defined as inadequate analgesia/anesthesia following an epidural, spinal, or combined spinal epidural anesthesia. The precise incidence of failed block is unknown. Failed block may be caused by inadequate drug dosing, technical issues, or patient factors. If the volume and/or concentration of administered analgesics/ anesthetics are insufficient to adequately block the required spinal segments, pain relief will be incomplete. The dose of intrathecal anesthesia needed to obtain a satisfactory block for cesarean is independent of age, weight, height or body mass index. Failed block may also be caused by impatience (eg, underestimating the latency of the administered drug and not allowing sufficient time to pass before declaring the block as failed). Operator or equipment related technical issues may also result in a failed block. As an example, if the epidural or spinal needle tip is not properly positioned, the injected drug will not be delivered to the desired location. If the aperture of the epidural or spinal needle is not wholly within the epidural or intrathecal space, respectively, a portion of the injected dose may not reach the intended site. With continuous epidural techniques, despite proper needle placement, the epidural catheter tip may not find its way into the epidural space, or may come to rest too far unilaterally, or protrude through an intervertebral foramen. These situations are more likely to occur if too great a length of catheter is threaded through the needle. More commonly, the catheter is initially inserted correctly within the ϭϲ 

epidural space, but later moves out .Ideally, the length of epidural catheter inserted is sufficient to prevent inadvertent dislodgement, but not too great so as to minimize the likelihood of unilateral placement. In laboring patients, the optimal catheter length to insert into the epidural space appears to be 5 cm (21). Other technical causes of failed block relate to patient anatomy (eg, post-surgical scarring that inhibits the spread of medication administered into the epidural space). Some unusual causes of failed spinal anesthesia have been described, and include rare anatomic malformations such as dural ectasia, an abnormal ballooning of the thecal sac. Injection of local anesthetic into an isolated area of the thecal sac may limit drug exposure to the target neural tissue. Enlarged thecal volumes per se, even in the absence of dural ectasia or cysts, may cause dilution or poor distribution of the hyperbaric local anesthetic dose. Failure of a block due to an inactive drug is possible, although very unlikely, particularly for amidelinked local anesthetics, which are very stable molecules (22).

Pruritis. Pruritus is a common side effect of neuraxial opioid administration. As an example, in one series, Fentanyl (25 microgram) and bupivacaine (2 ml) were injected intrathecally, pruritus occurred in 100 percnt of parturients, and 45 percent required treatment. Pruritus does not occur after the administration of local anesthetics alone. The etiology appears to be modulation of nociceptive reception, not histamine release. Thus, treatment with an antihistamine is not indicated, but is often used for its soporific effects.The ideal treatment for neuraxial opioid-induced pruritus is a small intravenous dose of an opioid antagonist such as naloxone (40 to 160 microgrm ) or the opioid agonistantagonist nalbuphine (2.5 to 5 mg). Small doses of opioid antagonists are known to selectively reverse opioid side effects without affecting analgesia. A common approach is to administer 40 to 80 microgram naloxone intravenously. A single dose of naloxone sometimes prevents recurrent itching. Alternatively, the patient may be given intravenous patient-controlled analgesia (PCA), naloxone to allow self titrate 40 microgramevery five minutes (22). Nausea and vomiting. Nausea occurs commonly in laboring patients due to visceral pain. Epidural and spinal local anesthetic block effectively diminish or eliminate pain, but can also precipitate nausea and vomiting. The mechanism is a decrease in blood pressure causing hypoperfusion of the medulla or cephalad spread of opioids to the chemoreceptor trigger zone. The incidence of nausea and vomiting ϭϳ 

after neuraxial opioid is much greater with the relatively poorly lipid soluble morphine compared to more lipid soluble agents, such as sufentanil, because morphine tends to travel cephalad within the aqueous CSF. The optimal treatment for opioid-induced nausea is administration of an opioid antagonist such as naloxone or the opioid agonist-antagonist nalbuphine. Nausea and vomiting resulting from hypotension are treated by administration of vasopressors (23) Sepsis. Aseptic technique is important to minimize risk of infection. Epidural abscess or meningitis are uncommon complications of neuraxial block. Epidural abscess is more likely to occur after epidural techniques, whereas meningitis typically occurs after the dura has been punctured, either intentionally as part of a spinal anesthetic, or unintentionally as a complication of an epidural procedure.The most commonly isolated bacteria were mouth commensals. Presumably, droplet contamination from medical personnel was the source of the CSF infection, which argues for a mandatory policy of wearing masks during instrumentation of the neuraxis. Skin bacteria may also be introduced into the neuraxis during instrumentation, emphasizing the importance of meticulous skin cleansing prior to the procedure (24). Pneumochephalus. Introduction of air during placement of neuraxial block may result in acute onset of severe headache and other neurologic signs and symptoms. This relatively rare complication may occur when air, rather than saline, is used to identify the epidural space with the loss-of-resistance technique. If the dura is inadvertently punctured, air may be injected into the subarachnoid space. If the parturient is sitting, the onset of headache and other neurologic symptoms may occur within a few seconds, as the air rapidly ascends to the brain, where it exerts its irritating effects. Use of saline rather than air for the loss-of-resistance technique can minimize the likelihood of this complication (25).

ϭϴ 

Pharmacology of local anesthetics Most local anesthetic agents consist of a lipophilic group (aromatic benzene ring) connected by an intermediate chain via an ester or amide linkage to an ionizable group (e.g., a tertiary amine). Local anesthetics may therefore, be classified as aminoester or aminoamide compounds. The amino-ester local anesthetics are: procaine, chlorprocaine and tetracaine. The amino-amides consist of lidocaine, mepivacaine, prilocaine, bupivacaine, and etidocaine. The ester and amide local anesthetics differ in their chemical stability, biotransformation, and allergic potential. Amides are extremely stable agents, while esters are relatively unstable in solution. Local anesthetics are weak bases and are made available clinically as salts to increase their solubility and stability. Inside the body they exist as the uncharged base (unionized form) or as a cation (ionized form). The relative proportions of these two forms is governed by the pKa specific for each local anesthetic and the pH of the body fluids(26).

Pharmacologic structure of bupivacaine (27).

The primary mechanism of action of bupivacaine is blockage of voltage-gated sodium channels. The excitable membrane of nerve axons like the membrane of cardiac muscle fibres and neuronal cell bodies maintains a resting membrane potential of -90 to -60 mV. During excitation the sodium channels open, and a fast inward sodium current quickly depolarizes the membrane towards the sodium equilibrium potential (+40 mV). As a result of depolarization, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane towards the potassium equilibrium potential (about -90 mV) repolarization returns the membrane to the resting state. The trans-membrane ionic gradients are maintained by the sodium pump (27).Thus, there appears to be a single binding site for local ϭϵ 

anesthetics on the sodium channel. Sodium currents are reduced by local anesthetics because the drug-bound channels fail to open. Inactivation and anesthetic binding prevent the conformational changes that constitute the activation process by fully or partially immobilizing the channel. Pain impulses fail to traverse the drugged axon. Impulse activity entering the anesthetized region thus maintains its own failure (28).

The onset of sensory blockade following spinal block with bupivacaine is very rapid (within one minute); maximum motor blockade and maximum dermatome level are achieved within 15 minutes in most cases. Duration of sensory blockade (time to return of complete sensation in the operative site) averages 2 hours with or without 0.2 mg epinephrine. The time to return of complete motor ability averages 3.5 hours without the addition of epinephrine and 4.5 hours if 0.2 mg epinephrine is added (29).

The systemic absorption of local anesthetics is determined by the site of injection, dosage, addition of vasoconstrictor agent, and pharmacologic profile of the agent itself. The maximum blood level of local anesthetic is related to the total dose of drug administered for any particular site of administration (30). Local anesthetic solutions may frequently contain a vasoconstrictor agent, usually epinephrine, in concentrations varying from 5 to 20 ȝg. Epinephrine decreases the rate of absorption of certain agents from various sites of administration and thus lowers their potential toxicity. The peak blood level of bupivacaine is minimally influenced by the addition of a vasoconstrictor (31). Local anesthetics are distributed throughout all body tissues, but the relative concentration in different tissues varies. In general the more highly perfused organs show higher concentrations of local anesthetic drug than the less well perfused organs. In particular these agents are rapidly extracted by lung tissue, so that the whole blood level of local anesthetics decreases markedly as they pass through the pulmonary vasculature. The highest percentage of an injected dose of local anesthetic is found in skeletal muscle. (32).

The pattern of metabolism of local anesthetic agents varies according to their chemical classification. The aminoamide group including bupivacaine undergoes enzymatic degradation ϮϬ 

primarily in the liver. Bupivacaine has a long elimination half life for a local anesthetic (2-7 h) accompanied by a low plasma clearance (0.58 litres/minute); these tend to increase the risk of systemic toxicity. It was found that bupivacaine binds with plasma proteins to the extent of 7090% (29) Bupivacaine is metabolized in the liver via conjugation with glucuronic acid. The excretion of bupivacaine occurs via the kidney. Less than 5% of the unchanged drug is excreted via the kidney into the urine. The major proportion of the injected agent appears in the urine in the form of various metabolites (29).

Ϯϭ 

Factors affecting intrathecal spread

The CSF of the vertebral canal occupies a narrow space (2-3 mm deep) surrounding the spinal cord and cauda equina enclosed by the arachnoid mater. As the local anesthetic solution is injected, it will spread initially by displacement of CSF. The next stage which may be the most crucial, is spread due to the interplay between the densities of both CSF and local anesthetic solution under influence of gravity. Gravity will be applied through patients' position (supine, sitting (32). Most plain solutions exhibit greater variability to effect and are less predictable, that the block may either be too low, inadequate for surgery, or excessively high causing side effects (33). Hyperbaric solutions are more predictable, with greater spread in the direction of gravity. The greater mean spread of hyperbaric solutions may be associated with an increased incidence of cardiorespiratory side effects, although this is not always the cause and may depend on the concentration of the glucose (34).Commercially available solutions contain up to glucose 0.8%, but most of the evidence shows that any concentration in excess of 0.8% will produce a solution that behaves in a hyperbaric manner, but with somewhat less extensive spread if the glucose concentration is at the lower end of the range (35). Clearly, it is impossible to change one of these factors without changing the other, but this is not always appreciated. Volume is an important determinant of the spread of isobaric solution and low volume injections (1-1.5 ml) may reduce spread. A change in dose will be accompanied by a change in either volume or concentration (36)

Both CSF and local anesthetics exhibit a decrease in density with increasing temperature (32).

ϮϮ 

Additives in itrathecal block Addition of glucose to the aqueous solution of local anesthetic increases viscosity as well as density (37). Studies of a wide range of local anesthetic drugs indicate that intrathecal spread is the same, no matter which one is used, as long as the other factors are controlled. Solutions containing vasoconstrictors spread in exactly the same way as those without, although block duration may be prolonged. Alkalinization of the solution injected in the does not increase spread, but does prolong duration (38).

The addition of other drugs, such as opioids or midazolam, has a dual effect. First, such additions are achieved by mixing the adjuvant and local anesthetic solutions, usually reducing the density of the latter. In theory this might make the mixture behave in a more hypobaric manner (50), but no effect has been shown in clinical practice, suggesting that the changes in density are small. The second effect is seen with opioids, which increase spread and delay regression, but opioids do so no matter what the route of administration either intrathecal or i.v. Presumably, this is a pharmacological enhancement of subclinical block at the limits of the local anesthetic's spread through the CSF (39).

Systemic reactions to local anesthetics involve primarily the central nervous system (CNS) and the cardiovascular system. In general the CNS is more susceptible to the systemic actions of local anesthetic agents than the cardiovascular system. The dose and blood level of local anesthetic required to produce CNS toxicity is usually lower than that which results in circulatory collapse (40). The initial symptoms of local anesthetic-induced CNS toxicity involve feelings of lightheadedness and dizziness, followed frequently by visual and auditory disturbances such as difficulty in focusing and tinnitus. Other subjective CNS symptoms include disorientation and occasional feelings of drowsiness. Objective signs of CNS toxicity are usually excitatory motor in nature and include shivering, muscular twitching, and tremors initially involving muscles of the face and distal parts of the extremities. Ultimately generalized convulsions of a tonic-clonic nature occurs. If a sufficiently large dose or a rapid Ϯϯ 

intravenous injection is administered, the initial signs of CNS excitation are rapidly followed by a state of generalized CNS depression. (40).

Local anesthetic agents can exert a direct action both on the heart and peripheral blood vessels. The primary cardiac electrophysiological effect of local anesthetics is a decrease in the maximum rate of depolarization in Purkinje fibres and ventricular muscle. This reduction in the maximum rate of depolarization is believed to be due to a decrease in the availability of fast sodium channels in cardiac tissues. High blood levels of local anesthetics will prolong conduction time through various parts of the heart, as indicated in the electrocardiogram by an increase in the PR, QRS and QT intervals, thus potentiating reentrant tachycardia . Extremely high concentrations of local anesthetic will depress spontaneous pacemaker activity in the sinus node, resulting in sinus bradycardia, heart block and sinus arrest (41).Local anesthetic drugs also exert a dose dependent negative inotropic action on the heart. The more potent agents as bupivacaine depresses cardiac contractility at the lowest concentrations (40).Local anesthetics may depress myocardial contractility by blocking the intracellular release of calcium from the sarcoplasmic reticulum (40). Local anesthetics exert a biphasic effect on peripheral vascular smooth muscle. Low concentrations of bupivacaine produce vasoconstriction, while high concentrations increase arteriolar diameter. At doses of local anesthetics that approach lethal levels, decrease in pulmonary artery pressure and pulmonary vascular resistance were seen with both types of local anesthetic drugs (41). The cardiotoxicity of bupivacaine appears to differ from that of other local anesthetics in the following manner: the dosage required for irreversible cardiovascular collapse is lower for bupivacaine than for other local anesthetic agents. Ventricular arrhythmias and fatal ventricular fibrillation may occur following rapid intravenous administration of a large dose of bupivacaine. The arrhythmogenic action of bupivacaine may be related to an inhibition of the fast sodium channels in the cardiac membrane (42). Pregnant patients may be more sensitive to the cardiotoxic effects of bupivacaine than non-pregnant patients .Acidosis, hypoxia and hypercarbia markedly potentiate the cardiotoxicity of bupivacaine (41). Cardiac resuscitation is more difficult and prolonged (30 - 45 minutes) following bupivacaineinduced cardiovascular collapse due to its high lipid solubility, requiring a long time for Ϯϰ 

redistribution (Mather et al, 2004).The time that the local anesthetic agent occupies the cardiac sodium channel is known as the dwell time. The dwell time for bupivacaine is 1.5 seconds, giving it insufficient time to dissociate from the sodium channels during diastole (0.4 seconds) resulting in accumulation of the drug and further cardiotoxicity (41).Toxicity of local anesthetics may be potentiated in patients with renal or hepatic compromise, respiratory acidosis, preexisting heart block, or heart conditions. Toxicity may also be potentiated during pregnancy, at the extremes of age, or in those with hypoxia and acidosis. The extent and degree of spinal anesthesia depends upon several factors including dosage, specific gravity of the anesthetic solution, volume of solution used, force of injection, level of puncture, and position of the patient during and immediately after injection. (7.5 mg or 1.0 ml) Bupivacaine Spinal has generally proven satisfactory for spinal anesthesia for lower extremity and perineal procedures including TURP and vaginal hysterectomy. (12 mg or 1.6 mL) has been used for lower abdominal procedures such as abdominal hysterectomy, tubal ligation, and appendectomy. These doses are recommended as a guide for use in the average adult and may be reduced for elderly or debilitated patients. Because experience with Bupivacaine Spinal is limited in patients below the age of 18 years, dosage recommendations in this age group cannot be made.

The aminoester may produce allergic-type reactions since these agents are derivatives of paraaminobenzoic acid. The amide local anesthetics are not derivatives of para-aminobenzoic acid and allergic reactions to them are extremely rare. Although aminoamide agents appear to be relatively free form allergic-type reactions, solutions of these agents may contain a preservative methyl paraben, whose chemical structure is similar to that of para-aminobenzoic acid (43).

In the patient with suspected local anesthetic toxicity, the initial step is supportive and symptomatic treatment in the form of stabilization of potential life threats, impending airway compromise, significant hypotension, and treatment of dysrhythmias and seizures. CNS manifestations, such as seizures, can be treated successfully with benzodiazepines (small increments of diazepam 2.5 mg) and barbiturates (e.g. phenobarbital) and 2 mg/kg of intravenous thiopental. Avoid use of phenytoin because it shares Ϯϱ 

pharmacologic properties (i.e. sodium channel blockade) with lidocaine and may potentiate toxicity. A recent report has suggested that the intravenous injection of 100 mL of 20% lipid emulsion may have a beneficial role in aborting central nervous system manifestations of bupivacaine toxicity (44). Maintain airway and respiration using O2 supply by face mask or endotracheal intubation and mechanical ventilation if needed. In the setting of local anesthetic induced cardiac toxicity, lidocaine has been used successfully in bupivacaine-induced dysrhythmias, but its additive CNS toxicity is still a major concern. Avoiding the use of class Ib anti-arrhythmic agents, such as phenytoin, mexiletine is crucial because they may worsen toxicity. In cardiovascular collapse, the use of adrenergic drugs with Į and ȕ agonist effect (e.g. ephedrine, epinephrine) is useful. Some case reports have indicated that the use of cardiac pacing and cardiopulmonary bypass may improve the outcome in the setting of prolonged resuscitation (45). Animal studies show that CPR (cardiopulmonary resuscitation) with a combination of vasopressin and epinephrine resulted in significantly better survival rates than either drug alone (42). In a study, combined boluses of glucose, insulin, and potassium were successful in reversing bupivacaine-induced cardiovascular collapse. However, the 2 units/kg dose of insulin used in this protocol may be challenging to use in clinical practice because of physicians' reluctance to administer such unusually high doses of insulin (46). Morris and Stacey (47) stated that tachyarrhythmias due to toxicity of bupivacaine are probably best treated by electrical cardioversion or with bretylium rather than lidocaine. In cases of refractory cardiovascular collapse caused by an overwhelming overdose of local anesthetic, The use of iv lipid is the treatment of choice in systemic toxicity of local anesthetics. In-vitro studies, animal studies, and human case reports have suggested IV fat emulsion to reverse the cardiac toxicity associated with local anesthetic overdose. The recommended dose is 1.5 mL/kg of 20% Intralipid IV bolus followed by a continuous infusion of 0.25 mL/kg/min for 30 minutes. This may be repeated 1 to 2 times if there is no evidence of clinical improvement. The rate of the infusion should be increased to 0.5 mL/kg/min for 60 minutes if blood pressure decreases. There are 2 proposed mechanisms by which lipid rescue therapy is thought to work. In-vitro studies suggest that the lipid infusion creates a lipid phase, or “lipid sink,” in the plasma to which lipophillic drugs such as local anesthetics can partition into. The second possible mechanism is reversal of mitochondrial fatty acid transport inhibition. It is believed that

Ϯϲ 

local anesthetics inhibit carnitine acylcarnitine translocase (CACT), an enzyme used in mitochondrial fatty acid metabolism and transport. Because fatty acids are involved in 80% to 90% of cardiac adenosine 5'-triphosphate (ATP) synthesis, inhibition of CACT may contribute to cardiac toxicity. Lipid infusion may increase the intracellular fatty acid content enough to overcome the inhibition of the CACT enzyme by the anesthetic.(48,49) Foxall and colleagues in (50) demonstrated the successful application of lipid emulsion infusion in the resuscitation of bupivacaine-induced cardiac arrest also known as “lipid rescue”. The proposed mechanism is that lipid infusion accelerates the decline in bupivacaine myocardial content (reduced tissue binding) by creating a lipid phase that extracts the lipid-soluble bupivacaine molecules from the aqueous plasma phase. (51) Weinberg's 2008 recommended dosing regimen for the use of lipid emulsion in humans: In cardiac arrest secondary to local anesthetic toxicity that is unresponsive to standard therapy, intravenous administration of a lipid such as Intralipid 20% is recommended in the following regimen: Administer 1 ml/kg over 1 minute. Repeat twice more at 3 to 5-minute intervals. Then once stability is restored convert to an infusion at a rate of 0.25 ml/kg/min, continuing until hemodynamic stability is restored (52).

Pharmacology of additives Deaths in regional anesthesia are primarily related to excessive high regional blocks and toxicity of local anesthetics. Reduction in doses and improvement in technique to avoid higher block levels and heightened awareness to the toxicity of local anesthetics have contributed to the reduction of complications related to regional anesthesia (43).

Additives are used in conjunction with local anesthetics for spinal anesthesia to quicken onset, to prolong duration and to enhance analgesia. Opioid receptors are dicovered in the dorsal horn and the brainstem. Binding of opioid receptors causes hyperpolarization of nerve membranes, which decreases nerve impulse transmission. Substance P and glutamate release are also inhibited.The addition of opioids to local anesthetics in spinals enhances and

Ϯϳ 

M studies suggest that opioids and local anaestthetic have a synergistic prolongs the duration of block. Many effect, but the mechanism is unknnown. Many types of opioids are used iin neuraxial blockade. Their onset and duration off action depends on their physicochemical properties.

Fentanyl. It is a synthetic phenylperidinee belonging to 4-anilopipridine series. It is a ssynthetic pure agonist at µ receptors. It is available as a the citrate salt in an aqueous preservative fr free solution containing 50µ g of fentanyl base per ml. It is a basic amine with pKa of 8.4, so that att physiological pH, only 8.4% of the drug is in its non-ionized form (52).The analgesic effect oof fentanyl and most G coupled opiate receptors with subseequent inhibition of opiates results via binding to G-protein adenyl cyclase, activation of K+ channels and inhibition of voltage-gated Ca C ++ channels, all of which decrease neuronal excittability (53)

C22 H28 N2 O Figure 2. Chemical structure of fenttanyl (3).

Spinal local anesthetics and oppioid mixtures.

Ϯϴ 

The addition of opioids to local anesthetic solutions for spinal anesthesia, enhances surgical anesthesia and provides postoperative analgesia. Intrathecal fentanyl has the advantage of decreasing visceral sensation and may prolong the duration of anesthesia (54). Mechanism of action of spinally administered opioids and local anesthetics. Opioids and local anaesthetics exert their antinociceptive effect in the spinal cord by different mechanisms. The µagonist, fentanyl, exerts its action by opening K+ channels and reducing Ca++ influx, resulting in inhibition of transmitter release. The µ-agonists also have a direct post-synaptic effect, causing hyperpolarization and a reduction in neuronal activity. Local anesthetics acts mainly by blockade of voltage-gated Na+ channels in the axonal membrane. (55). The lipid solubility of an opioid predicts its behaviour; opioids with low lipid solubility (hydrophilic opioids such as morphine) have a slow onset and long duration of action (56), whereas opioids with high lipid solubility (lipophilic opioids such as fentanyl) have a rapid onset but a short duration of action. Thus the lipid solubility of an opioid determines its access to the dorsal horn via: (1) diffusion through the arachnoid granulations and (57) diffusion into the spinal radicular artery blood flow (58)).

Ϯϵ 

Serious side effect of intrathecal opioids

It is dose-dependent early or delayed respiratory depression.. Risk factor of respiratory depression after intrathecal,and epidural narcotics: Elderly patients (older than 70 years of age),Impaired respiratory function,Poor medical condition,Higher epidural doses,Intrathecal technique,Water-soluble narcotics (e.g., morphine),Residual systemic opioids given preoperatively or during surgery,Use of other concurrent systemic sedatives, opioids, or antiemetics,Thoracic placement of epidural catheter (greater proximity to 4th ventricle.,Marked changes inthoracic-abdominal pressure (e.g., mechanical ventilation), Opioid-naïve or nontolerant parientes(59,60).

Opioids with relatively low lipid solubility can cause delayed respiratory depression with a peak incidence 3 to 10 hours after injection (61). Thus, close observation is recommended for 24 hours after injection (62). On the other hand, the high lipid solubility of lipophilic opioids such as fentanyl allows them to be absorbed close to the site of administration. Consequently lipophilic opioids do not migrate rostrally in the CSF and cannot cause delayed respiratory depression. However their high lipid solubility allows them to be absorbed systemically into blood vessels which may cause early respiratory depression as is commonly seen with systemic administration of opioids (63). In general, the side effects of epidural narcotics are no different than those seen with opioids given by other routes. These side effects include respiratory depression, hypotension, nausea and vomiting, pruritus, constipation, and urinary retention . With the exception of urinary retention, the incidence of narcotic-related side effects is dose-dependent. However, the incidence of side effects is higher with the intrathecal method . Further research is needed to compare the rates of narcotic-related side effects of epidural versus systemic narcotics utilized in the management of postoperative patients.. Naloxone reverses the respiratory effects of spinal opioids. In an apneic patient 0.4 mg IV. of naloxone will usually restore ventilation. Small incremental doses of naloxone (0.04 mg) may reverse the respiratory depression but not the analgesia. (64).

Nausea and vomiting are caused when the opioid reaches the vomiting centre and the chemoreceptor trigger zone in the medulla via CSF flow or the systemic circulation. Nausea can usually be treated with ϯϬ 

anti-emetics such as metoclopramide (5-10 mg) with ondansetron (4-6 mg). If severe, it can be treated with naloxone (0.2 mg increments, repeated if necessary) (65). Pruritus has an incidence of 30% and is the most common side effect occurring with spinal or epidural opioids. It is usually limited to the face and torso. Its mechanism is poorly understood but it appears to be centrally mediated due to the cephalad migration of the drug in the CSF, thus it is not common following intrathecal administration with fentanyl. (66). Urinary retention. The mechanism of spinal opioid-induced urinary retention involves inhibition of volume-induced bladder contractions and blockade of vesical reflex. Naloxone administration is also the treatment of choice although bladder catheterization may be required (67). Paralytic ileus. Intrathecal opioids may delay the recovery of gut motility. However combining intrathecal local anesthetics with opioids may hasten recovery of gut function due to segmental block of dermatomes T5-T12, antagonizing sympathetically mediated peristaltic inhibition while preserving vagal parasympathetic outflow (68).

ϯϭ 

Nalbuphine as an additive in spinal anesthesia:

Nalbuphine hydrochloride is a synthetic agonist-antagonist analgesic of the phenanthrene series. Chemically nalbuphine hydrochloride is 17-(cyclobutylmethy1)-4,5a-epoxymorphinan-36a,14-triol hydrochloride. It has a molecular weight of 393.91, and is soluble in H2O (35.5 mg/mL at 25oC) and ethanol (0.8%); insoluble in CHC13 and ether . Nalbuphine hydrochloride has PKa values of 8.71 and 9.96. The molecular formula is. The structural formula is :

The use of nalbuphine as an analgesic agent provides a number of advantages . Used as the sole opioid analgesic, It can satisfactorily cover mild to moderate pain with a low incidence of side effects. The ceiling effect of nalbuphine , which prevents it from supplying sufficient analgesia to cover the most severe discomfort , also prevents increasing sedation and respiratory depression as the dose is increased , potentially providing an increased safety margin in comparison to -agonists . When nalbuphine is used concurrently with -agonists (e.g. morphine, hydromorphone , fentany1), the benefits of both and - analgesia can be obtained , with simultaneously descreased incidence and serverity of the common -agonist side effects (pruritis , nausea/emesis , constipation , urinary retention , respiratory depiratory depression and undesirable sedation ). ( 69). The first study which used intrathecal nalbuphine was conducted by culebras x , et al (70) which injected ( 0.8 mg ) nalbuphine with bupivacain in comparison to morphine with bupivacaine in cesarean section and their study concluded that intrathecal nalbuphine 0.8 mg provides good intraoperative and early postoperative analgesia without side effects .

ϯϮ 

With respect to the neurotoxicity of intrathecal nalbuphine,in a sheep model using histopathological methods, that intrathecal nalbuphine was not neurotoxic. Even large doses (15–24 mg) of intrathecal nalbuphine were not associated with histopathological changes of the spinal cord. however, the smallest dose of intrathecal sufentanil was associated with inflammatory changes, axonal swelling, and shrunken neurons. With the largest dose of sufentanil, there were signs of meningitis and arachnoiditis(71).

Regarding the appropriate dose of intrathecal nalbuphine , the study conducted by Culebras X , et al ( 70) recommend the dose of 0.8 mg Nalbuphine to be injected intrathecally as they found that this is the best dose to improve the intraoperative analgesia and prolonges early postoperative analgesia , without increasing the risk of side effects . As they compared between the dose of ( 0.2 mg ) and the dose ( 0.8 mg ) and the dose ( 1.6 mg ) of nalbuphine and the dose ( 0.2 mg ) of morphine .

However , the study conducted by Akhilesh Kumar Tiwari , et al, ( 72 ) injected ( 0.4 mg ) Nalbuphine and found that dose provides good intraoperative and early postoperative analgesia with minimal adverse effects with hemodynamic stability . Tiwari AK, et al.,(72) which conducts a study comparing intrathecal Bupivacaine and a Combination of Nalbuphine and Bupivacaine for Subarachnoid Block . Their study concluded that:Nalbuphine hydrochloride (400 ȝg) significantly prolongs the duration of sensory blockade and postoperative analgesia without any side effect or complication when introduced intrathecally along with hyperbaric bupivacaine.Although , they injected 0.4 mg nalbuphine and we injected ( 0.8 mg ) but they agree with our study that nalbuphine has no side effects or complications when introduced intrathecally along with hyperbaric bupivacaine .

The study of

Culebras X, Gaggero G, et al ( 70) results agree with our study results ,

ϯϯ 

This study compared between advantages of Intrathecal nalbuphine and Intrathecal morphine , after cesarean delivery ,And evaluated postoperative analgesia and adverse effects . It found that the best dose of Nalbuphine to be injected is 0.8 - 1.6 mg. This study suggests that intrathecal nalbuphine 0.8 mg provides good intraoperative and early postoperative analgesia without side effects. However, only morphine provides long-lasting analgesia.

IMPLICATIONS : Small doses of intrathecal nalbuphine ( 0.4 mg ) or ( 0.8 mg ) mg produce fewer adverse effects , such as pruritus and postoperative nausea and vomiting, compared with intrathecal morphine. This may allow earlier discharge of patients from the recovery room culebras x , et al (70) ; conducted that , There was no maternal or newborn respiratory depression. Neonatal conditions (Apgar scores and umbilical vein and artery blood gas values) were similar for all groups , as it compared multiple doses of nalbuphine (0.2 mg ) , (0.8 mg) and

( 1.6 mg ) with ( 0.2

mg ) morphine .

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66.Battacharyya R and Dutta B (2007): Postoperative analgesia with local anesthetic and opioid combinations using double space CSE technique. Indian Journal of Anesthesia; 51 (5):409-414

67.Meyboom RHB, Brodie-Meijer CCE, Diemont WL and Van Puijenbrock EP (1999): Bladder dysfunction during the use of tramadol. Pharmacoepidemiology and Drug Safety; 8:63-64.

68.Chaney MA (1995): Side effects of intrathecal and epidural opioids. Canadian Journal of Anesthesia; 42:891-903.

69. Charuluxananan Kyokong O., Somboonviboon W., Lertma-harit Ngamprasertwong P., et al., Nalbuphine versus propofol for treatment of intrathecal morphine-induced pruritis after cesarean delivery. Anesth Analg. 2001;93:162-5

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70.Culebras X, Gaggero G, Zatloukal J, et al.(2000): Advantages of intrathecal nalbuphine, compared with intrathecal morphine, after cesarean delivery: an evaluation of post operative analgesia and adverse effects. Anesth Analg. 2000;91:6

71. Stoelting (2006): Stoelting's anesthesia and co-existing disease. Anesthesia analgesia; 12:110-152.

72. Tiwari, Akhilesh Kumar MBBS, DNB1,*; Tomar, Gaurav Singh MBBS, DA; Agrawal, Jeetendra MBBS, MD:intrathecal bupivacaine in comparison with a combinationof nalubphine and bupivacaine for subarachnoid block:A randomized prospective doule blind study . American Journal of Therapeutics nov-decem 2013 volume 20 issue-6-page 592-595.

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Research on Intrathecal Nalbuphine .

A Comparison between Post-operative Analgesia after Intrathecal Nalbuphine with Bupivacaine and Intrathecal Fentanyl with Bupivacaine after Cesarean Section

Hala Mostafa Gomaa(1), Nashwa Nabil Mohamed(2), Heba Allah Hussein Zoheir(3), Mohamad Saeid Ali(4).

1. Professor of Anesthesia, Kasr Al Ainy Hospital, Cairo University. 2. Assistant Professor of Anesthesia, Kasr Al Ainy Hospital, Cairo University. 3. Lecturer of Anesthesia, Kasr Al Ainy Hospital, Cairo University. 4. Assistant Lecturer of Anesthesia, Ahmed Maher Hospital, Cairo University.

Abstract:

Background: Adding intrathecal opioids to intrathecal local anesthetics to decrease their doses and provide hemodynamic stability are major goals during spinal anesthesia in cesarean section. Different opioids were used to select the one with the longest duration of analgesia and the least side effects. In this study; intrathecal nalbuphine was compared with intrathecal fentanyl as an adjuvant to hyperbaric bupivacaine in cesarean section. Patients and Methods: sixty female patients of ASA grades I and II presented for elective cesarean deliveries with spinal anesthesia were randomly allocated to 2 equal groups; Group F: 30 patients received intrathecal injection of 2 ml of 0.5% hyperbaric bupivacaine plus 0.5 ml fentanyl (25 µg); Group N: 30 patients received intrathecal injection of 2 ml of 0.5% hyperbaric bupivacaine plus 0.5 ml nalbuphine (0.8 mg). The onset of sensory and complete motor blockade, time of sensory blockade, duration of analgesia and motor blockade, fetal Apgar score, visual analog scale score, oxygen saturation, adverse effects and hemodynamic parameters were recorded intra-operatively and up to 4 hours postoperatively. The effective analgesic time was recorded. Results: The onset of complete motor block was significantly more rapid in fentanyl group than in nalbuphine group. The duration of postoperative analgesia was more prolonged in nalbuphine group but ϰϰ 

the difference was insignificant. No significant difference was found between both groups as regards the duration of sensory block, motor block, duration of analgesia, fetal Apgar score, visual analog scale score, hemodynamic parameters and oxygen saturation. Adverse effects were less common in nalbuphine group but the difference was insignificant. Conclusion: Either intrathecal nalbuphine 0.8 mg or intrathecal fentanyl 25 µg combined with 10 mg bupivacaine provides good intraoperative and early postoperative analgesia in cesarean section.

Key Words: Intrathecal; nalbuphine; bupivacaine; fentanyl; cesarean section.

Introduction: Spinal anesthesia for cesarean delivery is the best anesthetic technique as it is simple to perform with rapid onset of anesthesia and complete muscle relaxation. Lower incidence of failed block, less drug doses, minimal neonatal depression and decreased incidence of aspiration pneumonitis are added advantages of spinal anesthesia.(1,2) Intrathecal opioids are synergistic with local anesthetics and intensify the sensory block without increasing the sympathetic block. They are commonly added to local anesthetics for potentiating their effects, reducing their doses and thereby; reducing their complications and side effects and offer hemodynamic stability. They also prolong the duration of post-operative analgesia. (3) Fentanyl is a lipophilic opioid with a rapid onset following intrathecal injection. It doesn’t migrate to the 4Th ventricle in sufficient concentration to cause respiratory depression. It is commonly added to intrathecal bupivacaine in cesarean delivery by many anesthesiologists (2, 4 - 8). It improves quality of anesthesia without producing significant side effects, improves postoperative analgesia and hemodynamic stability(9). Nalbuphine, a mixed agonist–antagonist opioid, has a potential to attenuate the mu-opioid effects and to enhance the kappa-opioid effects. It was synthesized in an attempt to produce analgesia without the undesirable side effects of a ȝ agonist. Also, its combination with µ agonist opioids was tried by many researchers(10-12) to decrease the incidence and severity of the common µ-agonist side effects (respiratory depression, undesirable sedation, pruritus, nausea, vomiting and urinary retention). Meanwhile, the benefits of both Ƹ and µ analgesia can be obtained. Few studies had investigated intrathecal nalbuphine with hyperbaric bupivacaine (13, 14) and as far as we know; no study had compared it with intrathecal fentanyl which is the opioid in common practice added to hyperbaric bupivacaine in cesarean section. The aim of work was to compare the intra-operative and post-operative analgesic effect of intrathecal nalbuphine and intrathecal fentanyl as an adjuvant to bupivacaine during cesarean delivery. ϰϱ 

Patients and methods: After approval of the Local Ethics Committee and patients’ informed written consent, sixty female patients presented to Kasr Al-Ainy Hospital for elective cesarean deliveries with spinal anesthesia were enrolled in the study. Inclusion criteria: ASA physical status I or II with normal coagulation profile, age between 20 and 45 years, weight between 60 and 90 Kg and height between 160 and 180 cm were enrolled in the study. Exclusion criteria: ASA III or IV, patient refusal, infection at the site of injection, coagulopathy, anticoagulant medications, pre-existing neurological disease, uncooperative patients, cardiac or respiratory system failure, allergy to local anesthetics. The patients were divided randomly using computer generated number and concealed using sequentially numbered, sealed opaque envelope technique into two equal groups (each 30 patients): Group F and Group N. All patients were clinically assessed and routine preoperative investigations were done: CBC, PT, PTT, INR, liver function tests, kidney function tests, fasting blood sugar and ECG. Ranitidine 150 mg was administered orally before surgery. On arrival to the operating room; monitors were applied: electrocardiography, non invasive blood pressure and pulse oximetry. A suitable peripheral vein was cannulated and I.V. Ringer solution 10 ml/kg/15 minutes (preload) was given to all patients before the procedure. All patients were put in the sitting position with leaning forward. Sterilization was done. Dural puncture was performed at L4–L5 interspace or L3- L4 with a 25 gauge Quincke spinal needle. The patients were divided equally into two groups according to the additive (fentanyl or nalbuphine), all patients were received the same amount of local anesthetic (2 ml 0.5% heavy bupivacaine). Group F (Fentanyl) n= 30: Thirty patients received intrathecal injection of 2 ml of 0.5% hyperbaric bupivacaine plus 0.5 ml fentanyl (25 µg). Group N (Nalbuphine) n=30: Thirty patients received intrathecal injection of 2 ml of 0.5% hyperbaric bupivacaine plus 0.5 ml nalbuphine hydrochloride (0.8 mg) {nalufin 20 mg in 1 ml ampoule, Amoun Pharmaceutical Co., Cairo, Egypt). Spinal injections were done by anesthesiologists who didn’t participate in recording patients’ data. Both patients and observers were blinded to the drugs given. Then, the patients were placed in the supine position with a wedge under the right hip to maintain left uterine displacement. Elevation of the head by a pillow and oxygen mask 5 liters/minute was applied. The following parameters were recorded intra-operatively: Continuous monitoring to the conscious level and oxygen saturation. The level of sensory block (assessed by pin prick) and motor block (assessed by Bromage scale; 0= none, 1 = just able to move the knee but not the hip, 2= able to move the foot only, 3= unable to move the knee or foot)(15) were continuously recorded until skin incision. Surgery began when the block reached T5 dermatome. Heart rate and blood pressure were measured noninvasively every 5 minutes. Atropine (0.01mg/kg) was given if H.R. decreased below 60/min. Intermittent doses of ϰϲ 

ephedrine 10 mg I.V. if the systolic arterial blood pressure decreased by more than 20% below preanesthetic level or less than 100 mmHg. Visual analogue scale (VAS) was recorded [It ranges from 0 indicating no pain till 10 indicating severe intolerable pain with variable degrees of ascending pain in between]. If VAS • 4; general anesthesia was given and the patient was excluded. The neonatal Apgar score at 1 min. after delivery was calculated by an attending pediatrician. Complications related to spinal block or drug allergy (hypotension, bradycardia, pruritus, nausea, vomiting, shivering, rash and bronchospasm) were recorded and managed. A urinary catheter was left in situ and removed 24 hours later. The following parameters were recorded postoperatively up to the time of the first analgesic dose: Continuous monitoring to the conscious level, respiratory rate and oxygen saturation. Sensory level and motor block were assessed every 15 minutes till complete recovery. Heart rate and noninvasive blood pressure were recorded after 2 and 4 hours. The duration of analgesia (from intrathecal injections to VAS greater than 0) was recorded. The time of the first analgesic dose was recorded (effective analgesic time: from intrathecal injection to VAS • 4). NSAIDs (non steroidal anti-inflammatory drugs) were given for analgesia to all patients scoring •4. Any complication was recorded and managed as before. In addition: for vomiting; metoclopramide 10 mg I.V. was given, for pruritus; pheniramine maleate 45.5 mg I.V. was given. For shivering; pethidine 20 mg I.V. Respiratory depression was defined as a respiratory rate of < 10 breaths/min. and hypoxia was defined as an oxygen saturation of < 95%.

Power analysis: Being the primary outcome, power analysis was based on the difference in duration of analgesia between fentanyl and Nalbuphine groups provided that we studied 30 cases in each arm. Our results showed that the mean ± SD of duration of analgesia was 155.8 ± 31 minutes in fentanyl group, while it was 166.7 ± 14 minutes in Nalbuphine group. If the true mean difference in duration of analgesia between the 2 drugs was similar to our calculated difference (11 minutes), we will be able to reject the null hypothesis with 89.9% power. Student’s t test was used in the analysis with type I error probability equals 0.05. Calculations were done using PS Power and Sample Size Calculations Software, version 3.0.11 for MS Windows (William D. Dupont and Walton D. Vanderbilt, USA). Statistical analysis: Results were expressed as means ± standard deviation of the means (SD) or number (%). Comparison between different parameters in the two studied groups was performed using unpaired t test. Comparison between categorical data was performed using Chi square test. The data were considered significant if p value was equal to or less than 0.05 and highly significant if p value < 0.01. Statistical analysis was performed with the aid of the SPSS computer program (version 12 windows). Results: Sixty patients completed the study. ϰϳ 

Group F (n=30): fentanyl is the additive to bupivacaine. Group N (n=30): nalbuphine is the additive to bupivacaine.

Table 1: Demographic data and duration of surgery of the two studied groups.

Characteristics Age (yrs)

Fentanyl (n=30) 26.33 ± 6.08

Nalbuphine (n=30) 26.97 ± 5.40

P Value 0.671 (NS)

Height (cm)

168.97 ± 5.22

170.30 ± 6.94

0.404 (NS)

Weight (Kg)

78.83 ± 8.26

81.53 ± 9.85

0.255 (NS)

Duration of surgery (min.)

53.00 ± 5.19

53.17 ± 4.82

0.898 (NS)

Data are expressed as means ± standard deviation. NS= p> 0.05= not significant.

There was no statistically significant difference among the two groups as regards: age, height, weight and duration of surgery (table 1).

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Table 2: Sensory block, motor block and duration of analgesia of the two studied groups.

Characteristics

Fentanyl (n= 30)

Nalbuphine (n=30)

p value

Onset of sensory block (min.)

1.64 ± 0.09

1.60 ± 0.10

0.131 (NS)

Onset of complete motor block (min.)

5.57 ± 0.23

5.72 ± 0.17

0.008**

2 Segment regression time of sensory block (min.)

122.33 ± 5.21

123.00 ± 5.66

0.637 (NS)

Duration of motor block (min.)

125.87 ± 20.17

125.33 ± 5.71

0.890 (NS)

155.83 ± 30.96

166.33 ± 14.02

0.096 (NS)

222.5 ± 28.46

231.83 ± 15.73

0.1215(NS)

Duration of analgesia (min) Effective analgesic time (min.)

Data are expressed as means ± standard deviation. NS= p> 0.05= not significant. **p< 0.01= highly significant.

No statistically significant difference was found between both groups as regards the onset of sensory block, 2 segment regression time of sensory block and duration of motor block (table 2). There was statistically significant more rapid onset of complete motor block in group F than in group N (table 2). The duration of analgesia and the effective analgesic time were more prolonged in group N than in group F but this wasn’t statistically significant (table 2).

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Fig. 1: Heart rate (beats/min.) of the two studied groups.

There was no significant difference in the heart rate between group F and group N (Fig. 1).

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Fig. 2: SBP (mmHg) of the two studied groups.

There was no significant difference in systolic blood pressure between group F and group N (Fig.2).

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Fig. 3: DBP (mmHg) of the two studied groups.

There was no significant difference in diastolic blood pressure between group F and group N (Fig.3).

ϱϮ 

Fentanyl

Nalbuphine

100.0

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Time in minutes Fig. 4: SPO2 (%) of the two studied groups.

No significant difference was found in oxygen saturation between group F and group N (Fig.4).

Table 3: Adverse effects and fetal Apgar score in the two studied groups. Characteristics

Fentanyl (n= 30)

Nalbuphine (n=30)

p value

Hypotension

8 (26.7%)

6 (20%)

0.542 (NS)

Neusea & vomiting

3 (10%)

1 (3.3%)

0.301 (NS)

Pruritus

1 (3.3%)

0 (0%)

0.313 (NS)

Shivering

2 (6.7%)

1 (3.3%)

0.554 (NS)

Fetal Apgar Score

8.83 ± 0.46

8.83 ± 0.38

1.000 (NS)

Data are expressed as means ± standard deviation or number (%). NS= p> 0.05= not significant.

ϱϯ 

The adverse effects were less in group N than group F but there was no significant difference between both groups (table 3).

Respiratory rates were similar for both groups. Maternal oxygen saturation to < 95% wasn’t observed.

Discussion:

Regional anesthesia is now more popular than general anesthesia during cesarean delivery because of the increased mortality rate associated with general anesthesia (16). Excessive high regional blocks and local anesthetics toxicity are the commonest causes of mortality associated with regional blocks. So, reduction in the doses of local anesthetics, the use of new techniques to avoid higher blocks and better management of local anesthetic toxicity are the new goals for decreasing mortality associated with regional anesthesia(2). Intrathecal opioids cause segmental analgesia by binding to opioid receptors in the dorsal horn of the spinal cord. They prolong the duration of analgesia without affecting motor or autonomic nervous function. Their combination with intrathecal local anaesthetics limits the regression of the sensory block seen with local anaesthetics alone. Respiratory depression is the most serious side effect of intrathecal opioids while pruritus is the commonest. Others include; nausea, vomiting, urine retention and sedation(17,18). In this prospective randomized double blind study, the postoperative analgesic requirements and the spinally mediated analgesic effects of bupivacaine (hyperbaric) 0.5 % in combination with fentanyl (25 µg) or nalbuphine (0.8 mg) in patients undergoing elective cesarean section were observed and recorded. As regards the onset and duration of sensory block; there was no statistically significant difference between group F and group N. The onset of complete motor block was more rapid with fentanyl than nalbuphine and this was statistically significant. This may be explained by the high lipid solubility and rapid tissue uptake of fentanyl more than nalbuphine, and this needs further studies. Also in the present study; no statistically significant difference was found between both groups as regards the duration of motor block, hemodynamics and oxygen saturation. Neither bradycardia nor oxygen desaturation was recorded. The duration of postoperative analgesia and the effective analgesic time were more prolonged in nalbuphine group than in fentanyl group with no statistically significant difference. As regards the side effects; they were less in nalbuphine group than the fentanyl group with no statistically significant difference. The fetal Apgar score showed no statistically significant difference between both groups. Intrathecal fentanyl is used commonly with heavy bupivacaine 0.5% for spinal and epidural anesthesia by many researchers (2 , 4 - 7). Kang et al.(7) combined it with heavy bupivacaine during cesarean section to ϱϰ 

provide adequate depth of anesthesia. The duration of complete analgesia was longer in (bupivacaine and fentanyl) group 146±47 min. versus bupivacaine alone 104±44 min. The incidence of pruritus was higher with fentanyl but shivering was less. This comparison was also done by Biswas et al.(5) in cesarean section and concluded the same results. Sivevski A. (19) had studied the combination of reduced dose of local anesthetics (9 mg of isobaric bupivacaine) with intrathecal opioids (fentanyl 20 µg) in comparison to higher doses of local anesthetics alone (13.5 mg of isobaric bupivacaine) during cesarean delivery. He concluded that adding intrathecal opioids to reduced dose of local anesthetics can produce adequate spinal anesthesia with minimum hypotension and decreased vasopressor requirements. Also, the increased incidence of emesis with the use of bupivacaine alone may be secondary to increased incidence of hypotension because the emetic effects are relieved after the administration of ephedrine and elevation of blood pressure. Obara et al.(8) and Chavada et al. (9)agreed with these results. They concluded that the addition of intrathecal fentanyl to hyperbaric bupivacaine decreased the required amount of intra-operative analgesics and improved quality of anesthesia without producing significant side effects. The first study which used intrathecal nalbuphine was conducted by culebras x et al.(14) who compared intrathecal morphine (0.2 mg) added to hyperbaric bupivacaine with different doses of intrathecal nalbuphine (0.2 mg), (0.8 mg) and (1.6 mg) added to hyperbaric bupivacaine in cesarean section and their study concluded that intrathecal nalbuphine 0.8 mg provides good intra-operative and early post-operative analgesia without side effects (no PONV or pruritus). Nalbuphine 1.6 mg didn’t increase efficacy but increased the incidence of complications. So, the dose 0.8 mg was chosen in this study. They also reported that the postoperative analgesia lasted significantly longer in the morphine group. There was no maternal or newborn respiratory depression and the neonatal conditions (Apgar scores and arterial blood gas values) were similar for all groups. Regarding the appropriate dose of intrathecal nalbuphine: Lin M.L. et al.(20) had compared intrathecal nalbuphine 400 µg added to hyperbaric tetracaine with intrathecal morphine 400 µg and concluded that intrathecal nalbuphine in a dose of 400 µg prolongs intraoperative and postoperative analgesia with fewer side effects. Culebras X.(14) recommended the dose of 0.8 mg nalbuphine to be injected intrathecally after cesarean delivery and explained their difference with Lin M.L. et al.(20) by the fact that they used a different patient population (non pregnant patients) and different local anesthetic (hyperbaric tetracaine). Mukherjee A. et al.(21) had studied 100 patients undergoing lower limb orthopedic surgery using subarachnoid block. They used different doses of nalbuphine intrathecally (200, 400 and 800) µg added to 0.5% hyperbaric bupivacaine. They concluded that the duration of sensory block and the duration of effective analgesia were prolonged with the doses 400 µg and 800 µg but the side effects were higher with the dose 800 µg. Fournier et al.(22) compared between intrathecal nalbuphine 400 µg and intrathecal morphine 160 mcg in old patients undergoing total hip replacement using continuous spinal anesthesia. They concluded that intrathecal nalbuphine produces faster onset of pain relief but the duration of analgesia is shorter than intrathecal morphine. Yoon et al. (23) compared between intrathecal (morphine 0.1 mg), (nalbuphine 1 mg) and (morphine 0.1 mg with nalbuphine 1 mg) in addition to 0.5% bupivacaine 10 mg in 60 obstetric patients undergoing ϱϱ 

cesarean section. They concluded that the duration of effective analgesia was longer with morphine alone and morphine added to nalbuphine than in nalbuphine group alone. The incidence of pruritus was significantly higher in morphine groups while nausea and vomiting were the same in all groups. Tiwari AK, et al. (13) had compared intrathecal nalbuphine 200 µg and 400 µg added to hyperbaric bupivacaine with bupivacaine alone. They concluded that the duration of sensory block and duration of analgesia were maximally prolonged with nalbuphine 400 µg without complications. In a randomized, double blind, controlled study done by Sapate M, et al.(24) on adding intrathecal nalbuphine to bupivacaine for patients undergoing infraumbilical surgeries, they concluded that intrathecal nalbuphine added to bupivacaine provides better quality of block and longer postoperative analgesia (8-9) hours than bupivacaine alone without any significant adverse effects. This long duration can be explained by doing the study in age group (50-70) years and by using higher volume of heavy bupivacaine (3 ml). As regards the neurotoxicity of intrathecal nalbuphine; it has been used in modern practice for more than 10 years without any reports of neurotoxicity(21). CONCLUSION: We concluded that either intrathecal nalbuphine (0.8 mg) combined with (10 mg) Bupivacaine or intrathecal fentanyl (25 µg) combined with (10 mg) Bupivacaine improves intraoperative analgesia and prolongs early postoperative analgesia in cesarean section.

References:

1. Rudra A, Halder R, Sen A and Kundu S. Efficacy of low dose propofol for control of emetic episodes during cesarean delivery with spinal anesthesia. Indian J Anesthesia 2004; 48: 31-34. 2. Bogra J, Arora N and Srivastava P. Synergistic effect of intrathecal fentanyl and bupivacaine in spinal anesthesia for cesarean section. BMC Anesthesiology 2005; 5:5. 3. Tan PH, Chia YY, Lo Y, Liu K, Yang LC and Lee TH. Intrathecal bupivacaine with morphine or neostigmine for postoperative analgesia after total knee replacement. Can J Anesthesia 2001; 48 (6): 551-56. 4. Bano F, Sabbar S, Zafar S, Rafeeq N, Iqbal MN, Haider S, Aftab S and Sultan ST. Intrathecal fentanyl as adjunct to hyperbaric bupivacaine in spinal anesthesia for cesarean section. JCPSP 2005; 16 (2): 87-90. 5. Biswas BN, Rudra A, Bose BK, Nath S, Chakrabarty S and Bhattacharjee S. Intrathecal fentanyl with hyperbaric bupivacaine improves analgesia during cesarean delivery and in early post-operative period. Indian Journal of Anesthesia. 2002; 46 (6): 469-472.

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