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steroid therapy.26 Weakening of connective tissue may also pre- (incidence <1:1000 cases), histamine release, nephrotoxicity,
cholestasis, and an interaction with nondepolarizing muscle
dispose to uterine rupture.
relaxants.145,146,147 Central venous administration of CyA may
Steroid therapy is continued during pregnancy at prepregnancy
result in hyperkalemia, coronary vasoconstriction, and adult
dosing, with high-dose therapy indicated for treatment of episodes
respiratory distress syndrome.148,149 Limiting i.v. infusion rates
of acute rejection. Augmenting steroids postpartum to cover
to 2 mg/kg over a period of one hour is recommended.148
˜˜rebound immunoresponsiveness™™ is a controversial issue.17,137
Both increases and decreases in cyclosporine blood levels can
With little evidence of beneficial effect, the current practice is to
occur during pregnancy.150 Cyclosporine A requirements may
continue baseline therapy postpartum. It is uncertain whether a
increase during pregnancy, from decreased bioavailability,
history of exogenous steroid administration, followed by surgical
altered tissue distribution, and increased metabolism.10,151,152,153
stress with no supplementation, precipitates acute adrenal insuf-
ficiency.138 In reality, few patients with suppressed adrenal func- The volume of distribution may be increased, but because of
increased red cell mass, a greater portion of any given dose is
tion and no steroid supplement develop hypotension following
red cell bound.154 This effect may be offset by increased circulat-
surgery. The diagnosis of adrenal insufficiency is primarily one of
ing sex steroids, which inhibit liver microsomes (cytochrome
exclusion. However, supplemental high-dose steroid therapy has



390
Chapter 22


Allogeneic Figure 22.1 Schematic representation of graft
Cell
rejection and the sites of action of the currently used
Class II HLA Class II HLA
immunosuppressive agents: azathoprine,
Antigen Antigen
corticosteroids, cyclosporine, and monoclonal
Cytotoxic
Helper T TC
TH antibodies. (From Flye, M. W. Immunosuppressive
T Lymphocyte
Lymphocyte
therapy. In Flye, M. W. (ed.) Principles of Organ
Macrophage Stimulating
Transplantation. Philadelphia: W. B. Saunders, 1989,
Lymphokine MONOCLONAL
ANTIBODIES pp. 155“75.)
Postantigenic Postantigenic
Differentiation Differentiation
Interleukin-1

Macrophage Interleukin-2
Cytotoxic
T Cell
CORTICOSTEROIDS TC
TH

CYCLOSPORINE
AZATHIOPRINE
6MP
6MP
AZATHIOPRINE
Proliferation
Proliferation
Cytotoxic
Differentiation
Factor
TH TC




Promote TC
TH
Differentiation
B lymphocytes
(antibody secretion)
γ “ Interferon (macrophage
activating factor)
Allogeneic
Activation
cell

Macrophage


GRAFT REJECTION




P-450 IIIA) and impair hepatic clearance of CyA.153 Interpatient incidence of preeclampsia.157,158 Cyclosporine is excreted in
variability in CyA pharmacokinetics following oral administra- human breast milk and breast-feeding is contraindicated due to
tion, may account for reports of no appreciable change in dosing the potential for immune suppression, renal toxicity, an effect on
schedules.155 Possible effects of the normal physiological changes growth, and possible carcinogenesis.159 However, given that the
of pregnancy on drug distribution, metabolism, and clearance concentration of CyA in breast milk is usually <10% of therapeutic
have been summarized elsewhere. blood levels, and that breast-fed infants have shown undetectable
Cyclosporine A readily crosses the placenta with fetal levels blood CyA levels, in the absence of detectable adverse effects
ranging anywhere from 10% to 50% of maternal levels.151 Fetal women taking CyA have been allowed to breast-feed their infants.
side effects are dose dependent and include an increased inci- Blood CyA levels must be monitored in the infant to ensure that the
dence of IUGR, prematurity, and low birthweight. The NTPR level of exposure is less than 5% to 10% of the therapeutic
dose.154,160,161
noted a low birthweight (<2500 g) in 49.5% and a very low birth-
weight in (<1500 g) 17.8% of 107 infants born to transplant Nephrotoxicity and hypertension complicate CyA therapy in
recipients taking cyclosporine during pregnancy.19 Intrauterine virtually every patient. Cyclosporine-treated mothers are more
growth restriction may be associated with a reduction in nephron likely to be hypertensive before pregnancy (51.7%) as compared
number and oligomeganephronia. Therefore offspring of organ with mothers treated with other regimens (18.5%). Three etio-
transplant women treated with CyA may have a theoretical risk of logic mechanisms have been postulated including: increased
renal impairment, due to IUGR and fetal nephrotoxicity.156 proximal renal tubular pressure, decreased filtration coefficient,
and vasoconstriction.162,163 Nephrotoxicity is manifested as a
Overall, the pregnancy success rate with CyA appears comparable
to that with azathioprine.7,19 There is evidence that CyA has dose-dependent decrease in maternal GFR, with decreased
adverse effects on endothelial cell function, lipoprotein meta- creatinine clearance, increased blood urea nitrogen and creati-
bolism, placental prostanoid production, and platelet function. nine, hyperkalemia, hyperuricemia, hypertension, and hyper-
A combination of these factors, and longstanding hypertension, kalemic hyperchloremic renal tubular acidosis. Renal function,
may contribute to placental insufficiency and account for a 30% fluid balance, and electrolyte levels should be monitored



391
5 Other disorders


closely. Concomitant administration of drugs known to have which can alter CyA levels seven to ten days later and potentiate
nephrotoxic potential and those dependent on renal elimination CyA-related side effects.
should be avoided.
Additional complications of CyA include: mild hepatic dys-
Azathioprine
function, pancreatobiliary complications, hypochromic anemia,
fatigue, hypertrichosis, gum hyperplasia, predisposition to Azathioprine in combination with prednisone was conventional
thromboembolic phenomena, and rarely a hemolytic-uremic- immunosuppressive therapy in transplant recipients from 1961
like syndrome. Glucose intolerance and hyperinsulinemia, until the introduction of CyA in 1978. The normal maintenance
which may progress to overt DM, is associated with an increased dose is 1“2 mg/kg, with a reduction required if bone marrow
risk of atherosclerosis “ a leading cause of death in long-term depression or liver toxicity occurs. Additional maternal effects
survivors of solid organ transplants.164,165,166 include: rashes, gastrointestinal manifestations, pancreatitis, and
Various neurologic sequelae have been reported in 20 to 50% of increased risk of neoplasm and infection. Reversible interstitial
pneumonitis has been reported as a hypersensitivity reaction.179
patients treated with CyA including tremor, seizures, cerebellar
dysfunction, encephalopathy, neuropathy, and motor deficit syn- Azathioprine crosses the placenta, achieving fetal blood concen-
dromes.167,168 Paresthesia of the distal extremities (especially trations that are 63% to 93% of those in maternal blood.180
hands) is more common than focal weakness, although evidence Theoretically, the fetus should be protected from the effects of
of combined demyelination and axonal damage has been azathioprine during the period of organogenesis as the fetal liver
reported.169 Most neurotoxic side effects of CyA are completely lacks the enzyme inosinate pyrophosphorylase, required for con-
reversible with drug withdrawal.167 version of the parent drug to its active metabolites. Fetal and
When considering regional anesthesia, document any existing neonatal effects include: bone marrow toxicity, IUGR, sepsis, tran-
neurologic deficit and avoid hypomagnesemia, which can sient lymphocyte chromosomal damage and concerns of devel-
potentiate CyA-induced neurotoxicity. Also, exercise care with oping malignancies, congenital anomalies, and infertility in the
patient positioning. Another concern is concurrent viral or oppor- next generation. Azathioprine may be associated with SGA babies.
tunistic central nervous system (CNS) infection, frequently pre- Mice exposed to 3 mg/kg of 6-mercaptopurine in utero had lower
rates of conception and increased fetal loss as adults (46%).181
senting with few clinical findings and reported in approximately
5“10% of transplant patients. Neurological complications of Human and animal studies show that azathioprine potentiates
succinylcholine-induced muscle relaxation182 and antagonizes
organ transplantation may also result from progression of the
underlying disease process, a complication of the surgical proce- nondepolarizing neuromuscular blockade by presynaptic inhibi-
dure, or as a unique feature of a specific transplant type.167 tion of the motor nerve terminal.182,183,184
The possibility exists of interactions between CyA and any drug
acting as a substrate for cytochrome P-450.170,171,172 A potential
Tacrolimus
for drug interactions with CyA has been described for macro-
lide antibiotics, azole antifungal drugs, Ca2 þ channel blockers Tacrolimus (Prograf ’, FK506) is the newest macrolide immuno-
(excluding nifedipine), histamine H2-receptor antagonists, non- suppressive agent introduced into clinical trials in April 1990. It
steroidal antiinflammatory agents, and any nephrotoxic drug. functions by inhibiting the synthesis of IL-2 and other lympho-
kines and causing T-cell activation and proliferation.185,186 The
Agents commonly used in anesthetic practice that demonstrate
modified pharmacodynamic action include benzodiazepines, pharmacokinetic profile is similar to CyA with P-450 liver enzyme
neuromuscular blocking agents, opioids, antibiotics, and propo- metabolism, but tacrolimus does not require bile acids for solu-
fol. Isoflurane decreases the rate of absorption of CyA by reducing bilization and absorption. Advantages over CyA include greater
gastric emptying and absorption from the proximal small potency, a hepatotrophic effect, increased steroid-sparing and
bowel.173 Oral doses should be given 4“7 hours preoperatively, less hypertension, hypercholesterolemia, hyperuricemia, or ser-
as the formulation contains olive oil, castor oil, or corn oil, and ious infections. The incidence of new-onset DM, nephrotoxicity,
represents a significant risk if regurgitation and aspiration should and gastrointestinal tract complaints with tacrolimus is similar to
that of CyA.187 Neurologic complications include seizures, central
occur. In addition, the desired therapeutic blood levels may not
be achieved if given outside of this time interval. Cyclosporine has pontine myelinolysis with dysarthria, and motor disturbances,
which resolve with dose reduction.188 Headache and insomnia
been shown to prolong nondepolarizing neuromuscular block-
ade,145,146,174,175,176,177 from a combined effect of the parent drug, are other common dose-related complaints. Animals immuno-
causing inhibition of Ca2 þ entry into the muscle cell, and suppressed with tacrolimus, when compared with CyA, develop
Cremophor’, which interferes with drug binding. This increases more significant coronary artery disease over just four weeks in
the transplanted and native heart.189
the concentration of nondepolarizing drugs at the neuromuscular
junction. Cyclosporine A has been reported to improve analgesia Tacrolimus crosses the placenta, and umbilical cord concentra-
from fentanyl in a dose-dependent manner and to increase pen- tions are approximately 50% of maternal concentrations. Transient
tobarbital hypnosis.178 The clinical significance of this data is unexplained hyperkalemia, which resolves spontaneously within
uncertain. 24 to 48 hours, has been reported in the newborn of liver transplant
recipients taking tacrolimus during pregnancy.131 As with other
The potential for CyA and anesthetic agents to interact is impor-
tant, because many anesthetics cause liver enzyme induction, immunosuppressive agents, therapeutic dosing of tacrolimus has



392
Chapter 22


demonstrated no teratogenic activity in humans. In a limited num-
Table 22.14 Antenatal assessment of the transplant recipient
ber of published reports, birthweights are normal for gestational
age, which may be a result of steroid withdrawal or it may represent 1. Maternal problems
an intrinsic property of tacrolimus.131,132  Pregnancy
 Renal dysfunction: monthly urine cultures, treating
asymptomatic infections, monitoring BP, proteinuria,
Mycophenolate mofetil
and weight every 2“4 weeks
Mycophenolate mofetil use for immunosuppression after renal  Hypertension/preeclampsia: change hypotensive drugs to
transplantation has increased from 11.9% in 1995 to 79.6% those tolerated during pregnancy, abolishing ACE-inhibitors
in 2002.190 Mycophenolate mofetil is rapidly absorbed after and angiotensin II receptor antagonists
oral administration and is hydrolyzed to mycophenolic acid.  Monitoring of most common viral infections: titers of anti CMV
Mycophenolic acid is a reversible inhibitor of the enzyme inosine IgG and IgM every three months; test for toxoplasmosis every six
monophosphate dehydrogenase, blocking de novo purine bio- months; cervical culture for herpes infection before delivery
synthesis, essential for lymphocyte proliferation. In 2002, the  Screen for gestational diabetes
NTPR reported poor fetal outcomes after mycophenolate mofetil  Coexisting systemic disease process
exposure during pregnancy.125 Due to the long half-life of the drug,  Transplant surgery-related
proven teratogenic potential in animals, and lack of human data, 2. Immunosuppressive therapy
current recommendations are to withdraw mycophenolate mofetil  Monitor drug levels, modifying dosages according to
six weeks before conception in transplant recipients planning pharmacokinetic changes during pregnancy
a pregnancy.191,192,193  Complications, toxicities, adverse reactions
 Drug interactions
3. Graft function
Sirolimus
 Detection of acute/chronic rejection, ischemia, or failure
Sirolimus (rapamycin or Rapamune’) is a relatively new immu-  Physiologic adaptations to pregnancy
nosuppressant and antiproliferative drug used to prevent rejec-  Laboratory and diagnostic studies
tion in kidney transplant recipients. Sirolimus is a macrolide 4. Fetal surveillance
antibiotic (˜˜-mycin™™ ) by-product of the bacterium Streptomyces 5. Monitoring pregnancy by obstetrician and transplant physicians
hygroscopicus, which inhibits the response to IL-2 and thereby as a high-risk pregnancy
blocks activation of T- and B-cells. The chief advantage of siroli-
mus over calcineurin inhibitors, like cyclosporine and tacrolimus,
evaluation should consist of a thorough history and physical
is that it is not toxic to kidneys. Sirolimus can be used alone or in
examination, and review of the patient™s medical records and
conjunction with calcineurin inhibitors and/or mycophenolate
personal diary with special attention given to assessment of
mofetil, to provide steroid-free immunosuppression regimes. Its
maternal antenatal problems, immunosuppressive therapy,
optimal role in immunosuppression has not yet been determined
and is the subject of a number of ongoing clinical trials.194 graft function, and fetal surveillance (see Table 22.14).
Spontaneous onset of labor with vaginal delivery is the ultimate
goal, with C/S reserved for obstetric indications only. In patients
Monoclonal and polyclonal antibodies in whom the transplanted kidney or pancreatic graft is placed in
Orthoclone OKT3’ is an anti-CD3 monoclonal antibody that can the pelvis close to the uterus, there is no evidence to substantiate
the fear of organ injury during vaginal delivery or dysfunction
cross the placenta. The NTPR has reported treatment of five
women with OKT3 during pregnancy with four surviving infants.19 from compression by the enlarging uterus. Dystocia is a rare
complication.195 The patient should be encouraged to deliver in
The effect of polyclonal antibodies on the developing fetus is
a hospital-based setting that is equipped with a high-risk mater-
unknown but the immunoglobin component would be expected
nal and fetal monitoring unit and an intensive care facility.
to cross the placenta.
Tocolytic therapy for managing preterm labor includes magne-
sium, nifedipine, and beta agonists (terbutaline and ritodrine).
Anesthetic considerations for labor These medications are probably safe for use in renal and liver
and delivery transplant recipients.196 There are no case reports discussing the
use of beta-agonists in the cardiac transplant recipient, but they
probably should not be used in this population.196 Indomethacin
General considerations
should be avoided as it may potentiate cyclosporine nephro-
toxicity.197 It is vital to maintain a good urine output periopera-
Collaboration of a multidisciplinary team is essential in the
antenatal assessment and peripartum management of the trans- tively, as any further renal insults from drugs or periods of low CO
may be additive and can cause rapid development of anuria.198
plant recipient. Preferably, the patient should be seen in consul-
tation by an attending anesthesiologist early in the third Aseptic technique is essential: handling all intravascular and
trimester, as preterm labor and delivery is common. The airway equipment with sterile gloves and using prophylactic



393
5 Other disorders


antibiotics is essential to protect the patient from nosocomial choice, as there are no adverse neonatal effects at this intubating
infections. Invasive procedures such as fetal monitoring with a dose. Correct hypercalcemia, if possible, prior to administration
of anesthesia with monitoring of ionized serum Ca2 þ, potassium,
scalp electrode, intrauterine pressure monitoring, placement of a
urinary bladder catheter, or central venous and arterial cannula- and magnesium, volume status, renal and cardiac function, and
tion carry an increased theoretical risk of infection in transplant avoid metabolic or respiratory acidosis, which raises the ionized
Ca2 þ concentration even further. Responses to anesthetic agents
recipients. However, there are no reports in the literature suggest-
ing an increased risk of these infectious complications in the are not predictable.
immunosuppressed pregnant patient,89 so one must weigh the
risk to benefit ratio. Endotracheal intubation via the orotracheal
Liver
route is preferable given the possibility of technical difficulty from
nasal mucosal edema, risk of epistaxis, and the potential for Specific peri-anesthetic considerations for patients with liver dis-
infection by diphtheroids and staphylococcal commensals from ease and the pregnant patient with significant hepatic dysfunc-
the nasopharynx and skin. tion are reviewed in detail elsewhere (see Chapter 14).
Transfusion practices should take into consideration the In the liver transplant patient, analgesia for labor and delivery
Rhesus titer and CMV status of the patient. Institutional practices or anesthesia for C/S can be administered as in the healthy
vary from administering only CMV-negative blood products to all parturient if liver function is stable and coagulation is within
transplanted patients or exclusively to the CMV-negative recipi- normal limits. The ˜˜healthy™™ transplanted liver is no more sus-
ent who has received a CMV-negative organ; white-cell filtering ceptible to potentially hepatotoxic drugs (e.g. halothane) than the
liver of a normal patient.199
the blood and platelets to prevent transmission of CMV carried in
the leukocytes; and/or irradiation to destroy T cells, which pro- Continuing evidence of portal hypertension, and the possibility
voke graft versus host disease. of large venous collaterals, is a relative contraindication for place-
Virtually all anesthetic techniques have been used successfully ment of an epidural catheter, with increased risk of vessel pene-
tration and possible hematoma formation.199 Mild to severe graft
in transplant recipients for labor analgesia and forceps-assisted or
surgical delivery. The anesthetic technique will depend on dysfunction from acute or chronic rejection, recurrence of hepa-
(1) obstetrical considerations; (2) evidence of graft dysfunction; titis, or malignancy, may lead to altered drug distribution, coagu-
(3) the use of drugs and techniques to minimize additional insult lopathy, and portal hypertension. This has implications for
or physiological trespass to the transplanted organ; (4) the pre- provision of regional anesthesia, variceal bleeding with Valsalva
sence of absolute or relative contraindications to regional anes- maneuvers or insertion of a nasogastric tube, decreased anes-
thesia; and (5) individual preferences. Continuation of aspirin, thetic requirements, maintenance of hepatic blood flow, and
azathioprine, and dipyridamole in the peripartum period could avoidance of potential hepatotoxins.
theoretically affect platelet adhesiveness, but in the absence of The disposition and pharmacological effects of drugs in
overt platelet dysfunction most clinicians would not consider patients with chronic liver disease and the ability of the newly
these a contraindication to the use of regional anesthesia. transplanted liver to metabolize and eliminate drugs are poorly
Routine immunosuppressive therapy should be continued, while described. Caution should be exercised in the administration of
monitoring for signs of toxicity. The anesthetic problems asso- all agents, as the pharmacokinetic and pharmacodynamic prop-
ciated with long-term steroid, azathioprine, CyA, or tacrolimus erties of each drug depend on a composite of different factors
therapies are summarized in Table 22.15. including: altered graft function (rejection, recurrence of the pri-
mary disease process, nonspecific hepatocellular damage, or cho-
lestasis), persistent pathophysiologic changes characteristic of
Kidney and pancreas“kidney
end-stage liver disease, and drug interactions or toxic effects of
Coexisting systemic disease and residual physiologic alterations of the immunosuppressive therapy. Possible effects of the normal
end-stage renal disease may have a pronounced impact on physiological changes of pregnancy on drug distribution, meta-
bolism, and clearance have been summarized elsewhere.200
anesthetic management in this group of women (see Table 22.7).
In addition, patients should be monitored appropriately (see Hepatic extraction of morphine, fentanyl, and vecuronium is well
handled by the newly transplanted liver.201 In one study, morphine
Table 22.5) and graft function optimized (see Table 22.16).
Ischemic renal injury and potential nephrotoxins should be use following liver transplantation was significantly reduced for
72 hours compared to patients following liver resection.202 There
avoided. Deterioration of renal function may necessitate the use
of hemodialysis, with its inherent complications. Patients with a were no differences in pain or sedation scores. Factors that most
history of CRF have a high incidence of viral hepatitis (types B, C, likely account for this difference include altered pain perception
and HIV). This may result in hepatic dysfunction in the recipient. (steroids, cerebrospinal fluid endorphins, low grade encephalo-
There is a potential for significant accumulation and prolongation pathy, liver denervation, CyA, personality traits), or persistent
of the effect of anesthetic agents dependent on renal metabolism pharmacokinetic and pharmacodynamic changes inherent in
and elimination. Caution should be exercised in the use of succinyl- end-stage liver disease. It has yet to be determined whether this
significant difference persists long term.202 Accumulation of active
choline for intubation in a patient with peripheral neuropathy or
hyperkalemia resulting from renal insufficiency, or CyA and ter- morphine metabolites with prolonged narcosis should be anti-
cipated in patients with impaired renal function.203
butaline administration. Cisatracurium is a good alternate



394
Chapter 22


 Proximal myopathy
Table 22.15 Complications and anesthetic considerations of
 Peptic ulcer disease, nausea and vomiting,
immunosuppressive therapy
pancreatitis
 Neurologic sequelae (tremor, seizures, cerebellar
Cyclosporine
 Poor wound healing
dysfunction, encephalopathy, neuropathy, motor
 Increased susceptibility to infection
deficit syndromes, fatigue)
 Drug interactions: reduction of plasma
 ARDS
cholinesterase activity
 Aspiration pneumonitis
 Antagonism of pancuronium effects
 Hypertension, vasoconstriction
 Accelerated atherosclerosis, hypercholesterolemia
 Nephrotoxicity and enhanced susceptibility to
Table 22.16 Achieving optimum function of the transplanted
renal insults
kidney
 Hyperkalemic hyperchloremic renal tubular
acidosis 1. Maintain a homeostatic environment (fluids, electrolytes,
 Hemolytic-uremic-like syndrome acid-base status, hematocrit)
 Glucose intolerance 2. Cardiovascular stability (systolic blood pressure 120“140 mmHg)
 Hyperkalemia, hypomagnesemia 3. Intravascular volume expansion to a CVP 12“15 mmHg
 Hepatic dysfunction and pancreatobiliary 4. Drug therapy: dopamine 2.5“5 mg/kg/min, mannitol 25 g i.v., lasix
complications 40“400 mg i.v.
 Hypertrichosis, gum hyperplasia 5. Avoid nephrotoxic agents
 Predisposition to thromboembolic phenomena 6. Anticipate alterations in drug pharmacokinetics and
 Increased neoplastic and infection risk pharmacodynamics
 Hypersensitivity reactions, histamine release 7. Recognize and treat rejection, infection, or acute tubular necrosis
 Drug interactions: (P-450 III A microsomal
enzymes)
Clinically, the pharmacokinetics of a prolonged infusion of pro-
 Prolongs nondepolarizing neuromuscular
pofol for 48 hours following liver transplantation are identical to
blockade
those in patients with no evidence of hepatic disease.204 In con-
 Increases fentanyl analgesia
trast, the human cytochrome P-450 monooxygenase system is
 Neurologic sequelae (seizures, central pontine
Tacrolimus
suppressed by propofol in vitro, which suggests that potential
myelinolysis, headache, insomnia)
drug interactions may exist between propofol and substrates,
 Hypertension, accelerated atherosclerosis,
such as CyA, which use cytochrome P-450 for drug metabolism.205
hypercholesterolemia

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