Drugs 2004; 64 (3): 223-236 0012-6667/04/0003-0223/$34.00/0

CURRENT OPINION

© 2004 Adis Data Information BV. All rights reserved.

Regional Anaesthesia in Pre-eclampsia Advantages and Disadvantages Nanda Gopal Mandal and Sridhar Surapaneni Department of Anaesthesia, Peterborough Hospitals NHS Trust, Peterborough, UK

Abstract

Pre-eclampsia is a multisystemic disorder that is characterised by endothelial cell dysfunction as a consequence of abnormal genetic and immunological mechanisms. Despite active research for years, the exact aetiology of this potentially fatal disorder remains unknown. Although understanding of the pathophysiology of pre-eclampsia has improved, management has not changed significantly over the years. Anaesthetic management of these patients remains a challenge. Although general anaesthesia can be used safely in pre-eclamptic women, it is fraught with greater maternal morbidity and mortality. Currently, the safety of regional anaesthesia techniques is well established and they can provide better obstetrical outcome when chosen properly. Thus, regional anaesthesia is extensively used for the management of pain and labour in women with pre-eclampsia. This article highlights the advantages and disadvantages of regional anaesthetic techniques including epidural, spinal and combined spinal-epidural analgesia, used as a part of the management of pre-eclampsia. The problems associated with general anaesthesia and controversies in relation to obstetric regional anaesthesia are discussed.

Pre-eclampsia is the most common and poorly understood complication of pregnancy. Anaesthetists play an important role[1] in the peripartum care of these high-risk patients by providing analgesia for labour pain, anaesthesia for operative or instrumental deliveries, and postoperative and supportive care in a high dependency or intensive care unit. 1. Pre-eclampsia and Eclampsia 1.1 Definitions

Pre-eclampsia has been classically described as the triad of new-onset hypertension, new-onset proteinuria >0.3 g/day and new-onset nondependent oedema during pregnancy, usually after 20 weeks of gestation. Current diagnostic criteria include the presence of hypertension and proteinuria. Although the oedema is a common finding, it is not included

in diagnostic criteria. There is little agreement in the diagnosis of what constitutes high maternal blood pressure and thus the diagnosis of pregnancy-induced hypertension is inherently inaccurate. During pregnancy, hypertension is diagnosed when blood pressure is ≥140/90mm Hg, or when there is a rise of ≥30mm Hg systolic or ≥15mm Hg diastolic blood pressure over baseline, or an increase in mean arterial pressure of ≥20mm Hg or a mean arterial pressure above 105mm Hg. Blood pressure recording should always be repeated after an interval of at least 4 hours in order to confirm the diagnosis.[2] The occurrence of convulsions and/or coma unrelated to coincidental neurological diseases in a preeclamptic woman is called eclampsia. The convulsion is generalised in character and appears before, during or after delivery. Late postpartum eclampsia (48 hours to 4 weeks postpartum) accounts for 25% of all postpartum cases.[3]

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1.2 Aetiopathology of Pre-eclampsia

The actual aetiology of pre-eclampsia and sequence of events remain unknown. It is a multisystem disease because there is a functional imbalance between endogenous vasodilators and vasoconstrictors. Intense vasoconstriction causes organ hypoperfusion and ischaemic damage that affects nearly every major organ system. The current hypothesis has linked genetic makeup and immunological response in the genesis of pre-eclampsia.[2,4] It has been suggested that the presence of multiple genetic variants (including human leucocyte antigen-G, tumour necrosis factorα, angiotensinogen, factor 5 Leiden mutation, methylenetetrahydrofolate reductase, nitric oxide synthase gene and β2 adrenoceptor gene) in association with environmental factors, may predispose the development of pre-eclampsia.[2] Activation of the immune system results in increased production of inflammatory mediators. These mediators are thought to be responsible for generalised vasculitis and endothelial cell dysfunction. Pre-eclampsia has been described as a two-stage disorder. The first stage consists of the reduced placental perfusion, which is thought to be responsible for the increased production of vasoactive compounds. The second stage is the response to the decreased perfusion that leads to the maternal syndrome affecting both the woman and the fetus. Intense vasospasm in pre-eclampsia leads to contracted intravascular volume by as much as 30–40% (depending upon the severity of the disease) compared with normal pregnancy. Leaky capillaries and damaged endothelium cause a marked increase in interstitial fluid. This is exacerbated by hypertension and low plasma colloid osmotic pressure. Aggressive intravascular volume expansion with fluid and electrolytes increases the interstitial fluid (oedema) and puts a woman with pre-eclampsia at greater risk for the development of noncardiogenic pulmonary oedema. 1.3 Complications of Pre-eclampsia

Pre-eclampsia affects between 3% and 10% of all pregnancies.[5] It is a major cause of maternal and perinatal morbidity and mortality. The common maternal complications are coagulopathies includ© 2004 Adis Data Information BV. All rights reserved.

ing thrombocytopenia and disseminated intravascular coagulation, postpartum haemorrhage and HELLP (Haemolysis, Elevated Liver Enzymes and Low Platelets) syndrome. The CNS complications include cerebrovascular accident, hypertensive encephalopathy and convulsion (eclampsia). Cardiorespiratory complications are pulmonary oedema, congestive cardiac failure and myocardial infarction. Some patients may progress into acute renal failure, hepatocellular damage and septic shock. The HELLP syndrome[4] describes a severe form of pre-eclampsia (affecting 4–12% of pre-eclamptic women) and it is associated with high maternal (24%) and perinatal (30–40%) mortality. The incidence of eclampsia in pre-eclamptic patients is <1%. The leading cause of maternal death is intracranial haemorrhage followed by renal and hepatic failure (see table I). Recently, however, pulmonary oedema (iatrogenic fluid overload and acute respiratory distress syndrome) has been described as the main cause of death.[6] Pre-eclampsia is the second most common cause of maternal death after thromboembolic disease[3,7] and it accounts for 15% of all maternal deaths in the US.[3] The risk of death is increased with increasing maternal age, gestational age between 20–28 weeks, in black women, and after the first live birth and in the absence of prenatal care.[5] Fetal complications include prematurity with respiratory distress, intracranial haemorrhage, small for gestational age neonate and aspiration of meconium. The leading cause of intrauterine mortality is placental ischaemia followed by retardation of placental growth, placental disruption and acute infection of amniotic fluid. Pre-eclampsia accounts for 40% of iatrogenic premature deliveries and 20–30% of perinatal mortality.[9] Table I. Causes of maternal deaths in pre-eclampsia (reproduced from Gatt,[8] with permission from Elsevier Science) Cause

Maternal deaths (%)

Cerebral haemorrhage

30–40

Pulmonary oedema

30–38

Cerebral oedema

19

Renal failure

10

Coagulopathy

9

Airway obstruction

6

Drugs 2004; 64 (3)

Regional Anaesthesia in Pre-eclampsia

2. Regional Anaesthesia in Pre-eclampsia Both regional and general anaesthesia has been used safely in patients with pre-eclampsia. Epidural, spinal (subarachnoid block) and combined spinalepidural (CSE) analgesia are the most effective and safest forms of pain relief available to women in labour. Regional anaesthesia has many advantages for obstetric operative procedures including maintenance of airway reflexes and spontaneous ventilation. General anaesthesia is associated with higher maternal mortality and morbidity.[6,7,10,11] 2.1 Risks Associated with General Anaesthesia 2.1.1 Difficult or Failed Intubation

The airway problems associated with general anaesthesia and their potentially fatal sequellae have been identified as the main reasons for anaesthesiarelated maternal mortality in the past. ‘Difficult airways’ in the presence of engorgement of laryngeal mucosa and airway oedema are not uncommon in pre-eclampsia. Friability of mucosa can also make repeated attempts at laryngoscopy progressively more difficult. Failed intubation in obstetric anaesthesia is estimated to occur in 1 in 280 patients compared with 1 in 2230 patients in the nonobstetric population.[12] 2.1.2 Aspiration

Patients are at high risk for pulmonary aspiration. A rapid sequence induction of anaesthesia and preanaesthetic chemoprophylaxis with histamine H2 receptor antagonists or proton pump inhibitor and nonparticulate antacid orally are mandatory to minimise the risk. 2.1.3 Increased Sympathetic Response

Women with pre-eclampsia demonstrate an increased sympathetic response to stress. Exaggerated hypertension associated with laryngoscopy, intubation and extubation could be detrimental and may lead to intracranial haemorrhage and heart failure.[13] Many agents including nitroglycerin, sodium nitroprusside, nifedipine, ganglion blockers (e.g. trimetaphan camsilate), β-adrenoceptor antagonists (e.g. esmolol), magnesium sulfate, opioids and lido© 2004 Adis Data Information BV. All rights reserved.

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caine can be used to attenuate this hypertensive response. 2.1.4 Drug Interactions

Interaction of muscle relaxants with magnesium sulfate can lead to prolonged neuromuscular blocking effects. Neuromuscular blockade monitoring with a nerve stimulator is desirable. 2.2 Advantages of Regional Anaesthesia Over General

The calculated relative risk of general anaesthesia compared with regional anaesthesia for caesarean section is 16.7.[10] It is recommended that a regional anaesthetic technique should be used whenever possible in preference to general anaesthesia. General anaesthesia is preferable when regional techniques are contraindicated or where they have been unsuccessful. The decrease in the anaesthesia-related maternal mortality rate over the years appears to be related to the increased use and improved safety of regional anaesthesia. Presently, about 87% of elective and 70% of emergency caesarean sections in the UK are performed under regional anaesthesia.[10,14] Of the elective caesarean section patients 78% receive spinal anaesthesia, 18% have CSE anaesthesia and 4% are managed with an epidural anaesthesia.[14] Although the regional techniques provide an excellent quality of labour analgesia and anaesthesia, they also suffer from potentially serious and lethal consequences. Therefore, skilled and experienced personnel should administer major regional neuraxial block in locations where appropriate resuscitation equipment and drugs are immediately available to manage potential complications. 3. Regional Anaesthetic Techniques for Pre-eclampsia Epidural, spinal and CSE anaesthesia are common regional procedures performed by anaesthetists. Together, they are called a central neuraxial block (CNB). In accordance with the American Society of Anesthesiologists’ guidelines[15] there are no overriding major reasons which proscribe the use of a spinal, epidural or CSE block. In the current literature, there is no definite suggestion as to advantages and complications of each technique in preDrugs 2004; 64 (3)

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3.1 Epidural Anaesthesia

Epidural anaesthesia is the most widely used technique for analgesia during labour.[16] A carefully administered, continuous lumbar epidural anaesthesia is now recognised as the best technique for the management of patients with pre-eclampsia.[17] The primary aim of this technique is to control labour pain or to provide anaesthesia for instrumental or operative deliveries. Epidural anaesthesia is also used to manage postoperative pain. 3.1.1 Advantages of Epidural Anaesthesia

Epidural analgesia attenuates the metabolic stress response of labour pain without affecting the frequency of uterine contraction.[18] It suppresses the sympathetic overactivity of pre-eclampsia and reduces the level of circulating catecholamines.[19] Together, they result in the improvement of the preeclamptic condition. Epidural anaesthesia has been used as a therapeutic option to control blood pressure during pregnancy and labour in patients with progressive, severe pre-eclampsia.[2,20] Neurally imposed vasoconstrictive tone of the placental arteries is abolished by epidural anaesthesia, and, as a result, placental circulation is improved. In the absence of hypotension, epidural anaesthesia significantly improves intervillous blood flow by about 70% in women with pre-eclampsia (see figure 1).[21] Epidural anaesthesia can provide excellent relief of labour pain with maximum maternal satisfaction. Thus, the use of systemic opioids, which depress ventilation, affect the preterm fetus and induce emesis, can be avoided. Furthermore, epidural anaesthesia can prevent precipitous delivery of a preterm or small for gestational age neonate, which can be associated with neonatal intracranial haemorrhage. Compared with general anaesthesia, epidural anaesthesia is associated with a smaller haemodynamic and neuroendocrine stress response during caesarean section.[22] A sudden drop in blood pressure following spinal anaesthesia caused by the rapid onset of a sympathetic blockade may result in a drop in uterine perfusion. Uteroplacental hypoperfusion may be avoided with epidural anaesthesia because © 2004 Adis Data Information BV. All rights reserved.

Pre-eclamptic patients

100 Percentage increase in mean intervillous blood flow (±SE)

eclampsia. The choice would depend upon maternal request, fetal factors, availability of resources and the preference of the anaesthetist.

90 80 70 60

Healthy patients

50 40 30 20 10 0 0.25% Bupivacaine 10mL 0.25% Bupivacaine 10mL or 2% chloroprocaine 10mL

Fig. 1. Percentage increase in mean intervillous blood flow values (± SE) after epidural anaesthesia for labour in healthy patients and patients with pre-eclampsia. The bars represent the standard error (reproduced from Shnider et al.,[21] with permission).

of a slower onset of sympathetic paralysis. Ideally, a slow, controlled induction of regional anaesthesia allows the increased capacitance of the vascular system, caused by the sympathetic blockade, to develop slowly and permits the anaesthetist to titrate the intravenous fluid carefully. The use of epidural anaesthesia in haemodynamically stable patients with pre-eclampsia can deliver a newborn with a higher Apgar score than general anaesthesia.[23] Caesarean section delivery after epidural anaesthesia produces fewer modifications of neonatal immune function compared with general anaesthesia.[24] 3.1.2 Disadvantages of Epidural Anaesthesia

Common disadvantages of using an epidural anaesthesia are slow onset of action, failure to work, hypotension and greater technical difficulty in an uncooperative patient. The incidence of postdural puncture headache is high after inadvertent dural puncture with a Tuohy needle.[25] Insertion of epidurals can be time consuming. Thus, its use in emergencies (like fetal distress), where caesarean section should be undertaken as quickly as possible (ideally within 30 minutes according to the UK National Institute for Clinical Excellence guidelines[26]), is more difficult. Life-threatening complications including total spinal, high block and local anaesthetic toxicity have been reported.[27] Other disadvantages of an epidural anaesthesia could be urinary retention and, Drugs 2004; 64 (3)

Regional Anaesthesia in Pre-eclampsia

rarely, infections like epidural abscess and meningitis.[27] A possible link between epidural analgesia and new-onset, chronic backache proposed by retrospective analysis[28] has been discounted by subsequent prospective investigations.[29,30] The clinically insignificant rise in body temperature after the induction of epidural analgesia for labour is not associated with maternal or fetal infection.[31,32] 3.2 Spinal Anaesthesia

The use of spinal anaesthesia in pre-eclampsia has long been controversial because of the rapid onset of its effect and the possibility of severe hypotension compared with epidural anaesthesia. However, retrospective analysis of data comparing spinal with epidural anaesthesia in patients with severe pre-eclampsia showed that the degree of fall of maternal blood pressure, the need for intravenous fluid, the requirement for ephedrine, and the maternal and fetal outcomes were similar in both groups.[33,34] A comparative study between spinal and epidural anaesthesia in patients with severe preeclampsia found no significant difference in ephedrine requirements between the groups.[35] A recent prospective study found that the incidence and severity of hypotension is less in severely pre-eclamptic patients compared with healthy paturients undergoing spinal anaesthesia for caesarian section.[36] 3.2.1 Advantages of Spinal Anaesthesia

The main advantage of spinal anaesthesia, which is technically quicker and easier (with a more secure endpoint) to perform, is rapid onset with complete motor and sensory block. It is as safe as an epidural anaesthesia but superior in terms of reliability.[35] Spinal anaesthesia is most commonly used for operative or instrumental deliveries. Spinal anaesthesia can also be used for ‘limited time’ labour analgesia using a small quantity of local anaesthetic with or without opioids. The addition of epinephrine (adrenaline) or clonidine can prolong the duration of spinal analgesia.[37] However, a recent study found that clonidine is ineffective in this respect.[38] A single, spinal injection using currently available local anaesthetics and adjuvant will not provide long-lasting analgesia for labour pain. © 2004 Adis Data Information BV. All rights reserved.

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3.2.2 Disadvantages of Spinal Anaesthesia

Spinal anaesthesia, in the absence of a spinal catheter, is unable to guarantee ongoing pain relief because there is no top-up facility to ensure the extension of anaesthesia or analgesia. This is important for subsequent prolonged labour or for instrumental or operative delivery. Although the successful use of a spinal catheter in a patient with preeclampsia has been reported,[39] it has not been accepted in universal practice. Immediate complications of spinal anaesthesia include hypotension, bradycardia and high block (including total spinal). Post-spinal hypotension should be treated promptly to maintain placental perfusion and oxygen delivery to the fetus. Hypotension can be managed with compression stockings, lateral tilt, oxygen supplement, bolus intravenous fluid and vasopressors. Ephedrine (which does not adversely affect uterine blood flow) is the vasopressor of choice in patients with pre-eclampsia.[4,40] Other vasopressors (e.g. metaraminol, phenylephrine, angiotensin II) have been used only in patients with uncomplicated full-term pregnancies.[41] The incidence of post-spinal headache is low when a spinal injection is given through a fine gauge pencil point needle. Infectious complications, including meningitis, are as rare as they are with epidural anaesthesia.[27] 3.3 Combined Spinal-Epidural Technique

The CSE technique most commonly involves the insertion of an epidural needle into the epidural space followed by the advancement of a spinal needle through the epidural needle into the subarachnoid space. A catheter is then passed into the epidural space after injection of the spinal dose. The CSE technique combines the reliability of spinal anaesthesia with the flexibility of an epidural. The injection of a small quantity of short-acting opioid (e.g. sufentanil, fentanyl) with or without a small quantity of local anaesthetic (e.g. hyperbaric bupivacaine) through the spinal needle could result in rapid and complete labour analgesia with minimal changes in blood pressure or motor function. This is one of the methods used to establish ambulatory epidural analgesia (AEA). AEA is a popular choice of labour analgesia because ambulation reportedly increases maternal Drugs 2004; 64 (3)

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comfort, increases the intensity of uterine contraction, avoids aortocaval compression, facilitates head descent and relaxes the pelvic musculature. Studies comparing CSE with low-dose epidural anaesthesia and AEA with or without ambulation failed to establish any difference in labour outcome.[42-44] However, ambulation can reduce the duration of labour.[44] Haemodynamic changes, quality of labour analgesia, and progress and outcome of labour following CSE are similar to those after epidural.[45,46] In the presence of a functional spinal blockade, it is difficult to know whether placement of the epidural catheter is optimal. It has been suggested that the CSE technique should be avoided in patients with severe pre-eclampsia because it may delay the identification of a poorly functioning epidural. This situation could be dangerous if an urgent caesarean section was then required. It is also prudent not to use the CSE technique in patients who are a poor risk for general anaesthesia (e.g. difficult airway or obesity) because the functional status of the epidural catheter can not be tested immediately. Theoretical concerns of subarachnoid migration of epidural catheter and shaving off of metallic particles as a result of passing one needle through another have been invalidated.[47,48] Fetal bradycardia following spinal opioids is due to rapid onset of maternal analgesia and is not normally associated with adverse fetal outcome.[49] The perceived advantages of the CSE technique over an epidural may not be clinically significant. The potential consequences of routine dural puncture (thereby breaching the dural barrier) including meningitis, postdural puncture headache and damage to the conus medularis should not be overlooked.[50] In spite of its limitations, the CSE technique has been successfully used for caesarean delivery and labour analgesia in women with preeclampsia.[51] However, this technique may not be suitable in emergencies where a quickly performed intervention is needed. 4. Contraindications of Regional Anaesthetic Technique Although, a CNB has many advantages over general anaesthesia, it can not be used in all circumstances especially in the presence of significant clot© 2004 Adis Data Information BV. All rights reserved.

ting defects, infection, patient refusal, fixed cardiac output state and uncorrected hypovolaemia. Since regional anaesthesia comes on more gradually, and sometimes more incompletely, general anaesthesia is the best choice when urgent delivery is required because of fetal distress. 5. Controversies Relating to Regional Anaesthesia There are several controversies in obstetric anaesthesia relating to regional anaesthesia. However, firm recommendations regarding the management of these difficult conditions are generally difficult to offer. Some of the controversial issues are discussed in this section. 5.1 Clotting Abnormalities in Pre-eclampsia and Central Neuraxial Block (CNB) 5.1.1 Thrombocytopenia and Platelet Function Abnormalities

A low platelet count is the common abnormality found in 10–25% of patients with pre-eclampsia.[52] Its incidence and severity being decided by the severity of the disease and coexisting conditions (such as placental abruption, HELLP syndrome and disseminated intravascular coagulation).[4] In preeclampsia, the normal life span of platelets is also reduced by more than 50%.[4] Other clotting tests, including prothrombin time, partial thromboplastin time and fibrinogen concentration, remain unchanged until the platelet count falls below 100 000/mm3.[53] Although the platelet count may indicate the severity of pre-eclampsia, there is no direct correlation between the platelet count and the incidence of regional anaesthetic complications. The risk of epidural haematoma is difficult to quantify and may occur spontaneously even in the absence of risk factors. It is generally recommended that a CNB should be avoided if the platelet count is <100 000/mm3 or if the bleeding time is prolonged.[54] However, the benefits of epidural analgesia in patients with pre-eclampsia are such that many would consider that a platelet count of ≥80 000/mm3 is compatible with a safely performed CNB.[53,55] Beilin et al.[56] failed to document any neurological complication in 30 patients who received epidural analgesia with platelet counts beDrugs 2004; 64 (3)

Regional Anaesthesia in Pre-eclampsia

tween 69 000 and 98 000/mm3. In a similar retrospective analysis,[57] no neurological complication was noted in 62 patients with HELLP syndrome who received either epidural or spinal anaesthesia. All of these patients had a platelet count between 19 000 and 143 000/mm3.[57] It has been suggested that the bleeding time should be routinely measured either in all patients with severe pre-eclampsia or in those with a low platelet count (<150 000/mm3). However, a critical review concluded that the bleeding time is not a useful predictor of the risk of haemorrhage.[58] An editorial in The Lancet commented that there was very little evidence to support the use of bleeding time as a diagnostic test before using a regional anaesthesia technique.[59] A significant negative correlation exists between the platelet count and bleeding time, and no woman can have a normal bleeding time when the platelet count is <50 000/mm3.[60] However, the bleeding time is an unreliable test and it is no longer recommended to determine the safety of performing a CNB. A normal thromboelastograph (TEG) can determine the safety of regional anaesthesia. The maximum amplitude (MA) of TEG, which measures platelet function, does not decrease until the platelet count falls below 70 000/mm3.[61] In another study, Orlikowski et al.[62] found that the MA of TEG remained normal until the platelet count decreased to <54 000/mm3. On the basis of their study, they suggested that a platelet count of 75 000/mm3 should be enough for adequate haemostasis. However, there is no clinical evidence that a normal MA correlates with safely performed regional anaesthesia. Thus, the ability to identify which patients with pre-eclampsia can safely receive an epidural anaesthesia remains to be seen.[63] The platelet function analyser-100 (PFA-100) specifically determines platelet function by calculating closure time. It has been found that closure time may be a more sensitive maker for bleeding time than the MA of TEG for patients with pre-eclampsia.[64] Using a PFA-100 it was found that in patients with pregnancy-induced thrombocytopenia, platelet function might be preserved when the platelet count is as low as 60 000/mm3.[65] It is apparent from the current literature that most anaesthetists will agree to use a CNB when the © 2004 Adis Data Information BV. All rights reserved.

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platelet count is as low as 80 000/mm3. Considering the enormous benefits of regional analgesia in women with pre-eclampsia, a CNB may be an option even if the platelet count is as low as 75 000/ mm3. However, there is no absolute platelet count cut-off below which a CNB can be considered unsafe. A platelet count of 75 000/mm3 that is rapidly decreasing, as seen in pre-eclampsia, may be riskier for a CNB, than a stable platelet count of 50 000/ mm3, as seen in idiopathic thrombocytopenic purpura. Thus, each patient should be individually assessed and then, based on medical history, physical examination and evidence of coagulopathy, the best anaesthetic plan can be made. In a review of 61 patients with spinal haematoma following a CNB, the haematoma was related to epidural rather than spinal anaesthesia in 75% of patients.[66] Of all those patients who received epidural anaesthesia, 88% had an epidural catheter inserted and approximately 50% of the patients developed epidural haematoma after catheter removal. So, where suitable and where the benefit of a regional technique takes precedence over the risk, spinal anaesthesia should be preferable to epidural because of the smaller needle used for spinal anaesthesia. Inserting a more flexible epidural catheter can reduce the risk of traumatic bleeding. If a woman develops a coagulopathy after an epidural catheter has been placed, the epidural catheter should be removed only after the coagulation status has been documented as corrected. Finally, the patients who receive a CNB must be monitored in the postpartum period to detect early neurological signs attributable to bleeding in the epidural space. 5.1.2 Aspirin and Regional Blockade

Low-dose aspirin is used to reduce the risk of recurrent pre-eclampsia. Isolated use of aspirin or nonsteroidal anti-inflammatory drugs in general is no longer considered a contraindication of a CNB.[67] Thus, an epidural catheter can be safely placed in patients taking low-dose aspirin.[53] Checking the bleeding time in patients taking aspirin is not justified as the bleeding time is no longer considered a valid test (as this test lacks specificity and sensitivity) for platelet function. The risk of epidural haematoma with the use of low-dose aspirin has not been quantified but in the Collaborative Drugs 2004; 64 (3)

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Low-dose Aspirin Study in Pregnancy (CLASP), there were no epidural or bleeding complications that could be attributed to the use of aspirin.[68,69] 5.1.3 Low Molecular Weight Heparins and Other Anticoagulants

Low molecular weight heparins (LMWH) are being increasingly used for the treatment and prophylaxis of venous thrombosis. The actual risk of spinal haematoma in women who receive LMWH while undergoing a CNB is difficult to estimate. However, a CNB on patients taking LMWH for thromboprophylaxis during pregnancy can be performed if a specific minimum time interval of 10–12 hours between the previous dose and the initiation of the block, and 2–4 hours between the removal of the indwelling catheter and the next dose is observed.[67] In case series, no complication following a CNB was noted in patients who received prophylactic LMWH.[70,71] Therapeutic doses of LMWH, oral anticoagulants, unfractionated heparin or thrombolytic agents contraindicate the use of regional anaesthesia.[27] 5.1.4 Magnesium

Magnesium sulfate used for the prevention of seizures in pre-eclampsia has both an anticoagulant and an antiplatelet effect. However, no influence on coagulation was found on TEG assessment.[72] Thus, magnesium administration should not affect the use of a CNB. 5.2 Regional Anaesthesia and Labour Outcome

Regional anaesthesia for labour became established in medical practice without a firm understanding of its effects on labour outcome. It can significantly affect the progress of labour by direct or indirect means. The motor block associated with a CNB has been considered to play an important role in altering the dynamics of labour by several mechanisms. The mother’s ability to push in the second stage of labour is compromised with motor blockade. Alteration of pelvic floor muscle tone may affect the rotation of the presenting body part predisposing to malposition. It was observed that by lowering the concentration of bupivacaine, and thus eliminating the degree of motor blockade, resulted in a significant reduc© 2004 Adis Data Information BV. All rights reserved.

tion in the frequency of malposition, instrumental delivery and caesarean section.[73,74] A loss of perineal sensation decreases the urge to push in the second stage of labour. It also causes interruption of Ferguson’s reflex (afferent signals initiated by distension of the vagina stimulate increased secretion of oxytocin). Sympathetic blockade and reduced circulating catecholamines can affect uterine contractions. Other indirect effects such as maternal hypotension can reduce uterine activity. Reduction in labour pain, decreased level of anxiety and alleviation of maternal distress as a result of an effective CNB may lead to loss of urgency, which may contribute to prolongation of labour. Despite numerous studies to verify the effects of epidural analgesia on the progress of labour and the mode of delivery, the debate continues. Most of these studies are poorly controlled for confounding variables and this, together with methodological and ethical difficulties, has resulted in selection bias. The best way to solve this problem is to conduct a prospective, randomised and double-blind study. However, this type of study with regard to epidural analgesia and caesarean delivery rate is difficult to perform. It is impossible to blind and the crossover between the epidural and nonepidural groups is difficult to prevent. In order to minimise bias relating to crossover between treatment groups, results of prospective studies are usually analysed in terms of assigned rather than received intervention. As a result of crossover, many patients assigned to the nonepidural group actually receive epidural analgesia, and many patients assigned to receive epidural analgesia do not receive it. Thus, the proportion of patients who receive epidural analgesia in the two groups becomes more similar with the larger crossover. In these situations, the intention-to-treat analysis clearly cannot compensate and it significantly reduces power. This problem was noted in a recent trial.[75] Although that trial concluded that an epidural has little effect on labour outcome, the power of the study was insufficient and could still be associated with a 14% difference in caesarean section rate. This is obviously important clinically.[76] Earlier studies reported that epidural analgesia was associated with prolonged labour, more instrumental deliveries and a higher rate of caesarean section.[77-79] However, several subsequent studies Drugs 2004; 64 (3)

Regional Anaesthesia in Pre-eclampsia

and meta-analyses have concluded that epidural analgesia is not associated with a higher caesarean section rate, although it may significantly prolong the second stage of labour and increase the rate of instrumental deliveries.[75,80-84] Hogg et al.[82] found that epidural anaesthesia use did not increase the frequency of caesarean delivery among women with severe hypertensive disease. In a similar, randomly assigned, prospective study of women with preeclampsia comparing patient-controlled intravenous opioid analgesia with intrapartum epidural analgesia, no significant difference in the caesarean delivery rate was noticed.[85] It is more likely that uncomplicated epidural analgesia using low-concentration local anaesthetic and opioid solutions does not have any significant deleterious effect on the first stage of labour, whereas the second stage of labour is prolonged. Although, the caesarean section rate may not increase, the incidence of malpositions and the rate of instrumental delivery could go up with epidural blockade. It has been suggested that active management of labour and delayed pushing in the second stage may prevent increases in instrumental deliveries with increased epidural use.[86,87] Currently, no conclusive evidence exists to indicate whether timing of analgesia related to cervical dilation affects labour and delivery outcome significantly.[88,89] Finally, the likelihood of caesarean delivery may vary according to obstetrical management practice as well as the population studied. 5.3 Composition of the Anaesthetic Mixture Used For a CNB

Commonly used local anaesthetics for epidural analgesia are low concentrations of bupivacaine, levobupivacaine and ropivacaine. Levobupivacaine and ropivacaine have been developed for clinical use as they are less cardiotoxic and neurotoxic. Bupivacaine has a long duration of action with a moderate motor block. It is highly protein bound with the lowest placental transfer. Ropivacaine is less cardiotoxic but marginally less potent than bupivacaine. At low concentrations, it may produce a lesser motor block than bupivacaine. However, a recent meta-analysis of 23 randomised trials found no significant difference in obstetrical or neonatal outcome between bupivacaine and ropivacaine.[90] © 2004 Adis Data Information BV. All rights reserved.

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The degree of motor blockade by local anaesthetics is related to their cumulative doses. Many other adjuncts or additives are combined with local anaesthetic to increase their efficacy and safety. These include opioids, epinephrine, sodium bicarbonate and others. Many of these drugs have dose-dependent systemic effects affecting both mother and fetus. Opioids have a dose-sparing effect on local anaesthetic.[91] It is easy to maintain analgesia with a subtherapeutic low concentration of local anaesthetic and opioids with minimal motor blockade. Opioids alone used epidurally or intrathecally can provide analgesia and, thus, could be useful as no effect on the progress of labour is to be expected. Nevertheless, they cannot provide satisfactory pain relief associated with perineal distension.[91] Epinephrine is commonly used with some local anaesthetics to reduce the peak plasma concentration and prolong the action of the local anaesthetic.[92,93] Although the fetal heart rate abnormalities due to an epidural local anaesthetic are reduced by epinephrine, it does not improve neonatal outcome.[92] Epinephrine absorbed systemically into maternal circulation inhibits uterine activity. Injection of epinephrine at 40 μg/h into the epidural space prolonged the duration of labour without affecting the fetal outcome.[92] Theoretically, epinephrine can reduce uteroplacental perfusion by increasing the vascular resistance. However epidurally used epinephrine did not change umbilical or uterine artery blood flow.[92,93] Epinephrine, fentanyl and sodium bicarbonate mixed with local anaesthetic decrease the time to surgical anaesthesia. This may be useful for establishing epidural anaesthesia quickly for operative delivery in emergencies.[94] In conclusion, epinephrine does not have any significant role when an epidural using low concentrations of local anaesthetic with opioids is being used for labour analgesia. Epinephrine may be useful when a large amount of local anaesthetic is injected to provide epidural anaesthesia. 5.4 Regional Anaesthesia and the Fetus

Regional anaesthesia can affect the fetus directly (as a result of the drugs reaching the fetal circulaDrugs 2004; 64 (3)

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tion) and indirectly (mainly as a result of maternal haemodynamic and physiological changes, e.g. hypotension, aortocaval compression, hypoventilation, hypercarbia etc). The assessment of effects of local anaesthetics on the fetus is based on the monitoring of the fetal heart rate and the measurement of fetal pH. Apgar score and neurobehavioural tests also allow an evaluation of effects of the drugs used on neonates. Epidural analgesia is associated with better neonatal acid-base status compared with systemic opioids.[95] This is because of better placental perfusion associated with epidural analgesia. Apgar scores are higher when a regional rather than a general anaesthesia is used for a caesarean section, when there is fetal distress.[23,96,97] Although a higher Apgar score was noted in infants whose mothers received regional anaesthesia compared with infants whose mother received general anaesthesia, the Neurologic and Adaptive Capacity Scores (NACS) were not statistically different between these two groups.[97] Recent studies using typical anaesthetic-opioid regimens as currently used show negligible neonatal drug concentrations and consequences.[98] Epidural analgesia does not affect the breastfeeding success rate.[99] Early maternal-neonatal bonding and adequate postoperative pain relief lead to greater success in breastfeeding. Thus, regional anaesthesia is preferable to general anaesthesia and adequate postoperative analgesia is desirable. The local anaesthetics and their metabolites (e.g. lidocaine, bupivacaine and its metabolite pipecolylxylidide) excreted via the breast milk do not affect the neonates.[100] Under normal maternal and fetal conditions, general and regional anaesthesia are almost identically useful with respect to neonatal well being after caesarean delivery. Subtle and inconsistent neurobehavioural residue may be present for a short time following general anaesthesia. However, in conditions where there is a compromised fetus (as in preeclampsia), the neonate may benefit from epidural anaesthesia more than from general anaesthesia.[101] © 2004 Adis Data Information BV. All rights reserved.

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5.5 Fluid Management and Preloading Before Regional Anaesthesia

Fluid administration is always a concern in preeclampsia and there is no solid basis for a rational strategy.[102] There is no consensus regarding most aspects of volume management in pre-eclampsia. A leaky capillary with low colloid osmotic pressure (due to protein loss) makes a patient with pre-eclampsia more susceptible to develop noncardiogenic pulmonary oedema (seen in about 2.9% of women with pre-eclampsia[103]). Maintenance fluid should be restricted to 80 mL/h or about 1 mL/kg/h to avoid fluid overload. A careful assessment of urine output and the clinical condition of the patient should be made before administering additional fluid. Preloading with crystalloid or colloid before administering regional anaesthesia remains controversial. A low plasma volume and cardiac output increases the likelihood of fetal distress and oliguria, particularly after vasodilatation following a regional technique. Women having low-dose epidural analgesia with low concentrations of local anaesthetics with opioids used for labour analgesia are haemodynamically more stable. Routinely, they do not require any fluid preloading.[104] Preloading with balanced crystalloid or colloid is recommended before a CNB is used for operative or instrumental delivery. Moderate preloading prior to vasodilator therapy minimises hypotension and improves cardiac output.[105] Preloading with 1 litre of Ringer’s lactate in patients with pre-eclampsia before spinal anaesthesia did not prevent maternal hypotension.[106] Although no technique totally eliminates the occurrence of hypotension, colloid administration is more effective than crystalloid.[107] If hypotension does occur, it can be treated with small fluid boluses (e.g. 250mL of crystalloid) to keep the blood pressure near normal. Maintaining systolic blood pressure at 80% or more of the baseline value is associated with only minor changes in uterine blood flow.[106] Bolus intravenous fluid before regional anaesthesia can inhibit uterine activity transiently.[108] The issue of invasive haemodynamic monitoring of patients with pre-eclampsia is a controversial topic. There may be a poor correlation between the Drugs 2004; 64 (3)

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central venous pressure (CVP) and left atrial pressure in pre-eclampsia.[109] A pulmonary arterial (PA) catheter may provide better information in these situations. There is insufficient data to demonstrate improvement in maternal, fetal and neonatal outcome with the use of a CVP or PA catheter. It is not necessary to use invasive haemodynamic monitoring in every patient with severe pre-eclampsia. However, in those with refractory oliguria (not responding to fluid treatment), refractory hypertension (not responding to vasodilatation and antihypertensive medications) and unresponsive pulmonary oedema, invasive haemodynamic monitoring may provide useful guidance for optimum fluid management. 6. Conclusion Pre-eclampsia remains a significant cause of maternal and perinatal mortality and morbidity. It is not entirely preventable and the only curative treatment is the delivery of the fetus or removal of the trophoblast and placenta. Multidisciplinary management is essential for conservative and supportive therapy. Anaesthetists play a significant role in this process. In spite of the problems, complications and controversies, CNBs play an important role in the management of pre-eclampsia. Regional anaesthesia is a perfect choice for women with pre-eclampsia provided all the risk factors are assessed and the patients are haemodynamically stable. Epidural analgesia should be instituted early for maximum benefits. CNB, preferably epidural, can provide the best form of analgesia with a high degree of maternal satisfaction. A CNB can also help to control blood pressure. The avoidance and prompt treatment of maternal hypotension is the most important measure in maintaining uteroplacental blood flow during obstetric regional anaesthesia. In the absence of significant hypotension, epidural anaesthesia can increase uteroplacental blood flow and thus oxygen delivery to the fetus. Modern techniques of epidural analgesia using low concentrations of local anaesthetics with opioids have contributed significantly to reduce the number of instrumental deliveries. A properly conducted CNB can improve maternal and fetal outcome compared with general anaesthesia. © 2004 Adis Data Information BV. All rights reserved.

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Acknowledgements The authors would like to thank Dr Balraj Appadu, Consultant Anaesthetist, Peterborough District Hospital for reviewing this manuscript. The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

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Correspondence and offprints: Dr Nanda Gopal Mandal, Department of Anaesthesia, Peterborough District Hospital, Thorpe Road, Peterborough, PE3 6DA, UK. E-mail: [email protected]

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