• Admir Hadzic, MD

        INTRODUCTION

Patients with coexisting severe systemic disease may be at a higher risk for perioperative complications related to surgery and administration of anesthesia. Regional anesthesia is often touted as beneficial in many patients who have pulmonary, cardiac, renal, and other disease. However, the physiologic changes that occur with various regional anesthesia techniques must be understood and viewed within the context of an individual patient’s pathophysiology so that the technique benefits the patient fully and reduces the risk of complications from the patient’ disease. This chapter focuses on the pathophysiology of several common systemic diseases frequently encountered by the regional anesthesiologist and discusses the interplay between common regional anesthesia techniques and patient disease.

        PULMONARY DISEASE

Surgical patients with coexisting pulmonary impairment are at risk for intraoperative or postoperative pulmonary complications, regardless of anesthetic technique.¹ However, increasing evidence suggests that regional anesthesia may be associated with improved pulmonary outcomes compared with those associated with general anesthesia.^2–4 A thorough understanding of respiratory physiology and the implications of regional anesthetic techniques is crucial to the safe and effective use of regional anesthesia in these patients.

Epidural & Spinal Anesthesia

Most of the pulmonary effects of neuraxial anesthesia are due to motor block of the intercostal and abdominal musculature. If a significant systemic uptake of local anesthetic occurs, some central and direct myoneural respiratory depression can also be seen, although this plays a minor role overall.³ Since neuraxial anesthesia produces a “differential” blockade of motor, sensory, and autonomic fibers, the degree to which respiratory function is impaired depends on the relative extent of segmental motor blockade. Using dilute concentrations of epidural local anesthetic may provide adequate sensory block as high as the cervical levels, while sparing the motor function of the respiratory muscles in the lower somatic segments.⁶ Achieving diaphragmatic paralysis via a phrenic nerve (C3 through C5) block in the absence of a total spinal anesthesia is difficult in practice, since even a sensory block as high as C3 will only produce a motor block at approximately T1 through T3.⁵ However, high neuraxial blocks may precipitate hypotension sufficient to decrease blood flow to the respiratory center in the medulla, leading to respiratory arrest.

        With higher levels of epidural or spinal anesthesia, chest wall musculature, and in particular the intercostal muscles, become segmentally weakened and contribute less to the respiratory effort. This in turn, may eventually lead to altered chest wall motion during spontaneous respiration. For instance, some studies have suggested that during high neuraxial anesthesia, the more compliant chest wall is retracted during inspiration and may actually display paradoxical rib cage motion.^7–8 Others, however, have found that epidural blockade to sensory levels of T6 or even T1 do not lead to rib cage constriction with inspiration and may in fact increase the contribution that chest wall expansion makes to tidal volume.^9,10 This may be explained by an incomplete motor block of high, intercostal muscles or the compensatory role played by the “accessory” muscles of respiration such as the anterior and middle scalene muscles.¹¹

        Lumbar epidural anesthesia does not impair resting minute ventilation, tidal volume, or respiratory rate.^12–14 Furthermore, functional residual capacity (FRC) and closing capacity appear to be relatively unchanged during lumbar epidural anesthesia.^15–17 Effort-dependent tests of respiratory function, such as forced expiratory volume in one second (FEVi), forced vital capacity, and peak expiratory flow rate, do exhibit modest decreases in the setting of lumbar epidural blockade, reflecting the reliance of these indices on intercostal and abdominal musculature.¹⁸ In contrast, the effect of thoracic epidural anesthesia on pulmonary mechanics is less clear, with studies showing both a decrease^14–19 and increase²⁰ in minute ventilation and tidal volumes. One volunteer study found that high thoracic epidural anesthesia (T1 sensory level) led to an increase in FRC of approximately 15% with no change in tidal volume or respiratory rate.¹⁰ This somewhat surprising finding may be explained by two mechanisms offered by the investigators. First, most volunteers exhibited a decrease in their intrathoracic blood volume, a physiologic occurrence confirmed by Arndt and colleagues.²¹ Second, the study also found that the end-expiratory position of the diaphragm was shifted caudally, which is possibly related to a relative increase in diaphragmatic tonic activity or a reduction in intraabdominal pressure. Thoracic epidural anesthesia results in a modest decrease in vital capacity (VC), FEV], total lung capacity, and maximal midexpiratory flow rate.¹⁵

        The ventilatory response to hypercarbia and hypoxia is preserved with neuraxial anesthesia.¹⁴ Partial pressures of both oxygen (Po₂) and carbon dioxide (Pco) are essentially unchanged during epidural or spinal anesthesia.¹⁰ In addition, bronchomotor tone is not altered to any significant degree, despite theoretical concerns of bronchoconstriction secondary to sympatholysis.²¹ Indeed, epidural anesthesia has been used successfully for high-risk patients with chronic obstructive pulmonary disease and asthma undergoing abdominal operations.^22,23

        Neuraxial anesthesia has been shown in a number of settings to lead to reduced postoperative pulmonary complications compared with general anesthesia. The reasons behind this are probably multifactorial, owing in part to superior analgesia, reduced diaphragmatic impairment, altered stress response, and a decreased incidence of postoperative hypoxemia.^24,25 Epidural anesthesia provides better pain control than general anesthesia for abdominal and thoracic surgery, which leads to reduced splinting, a more effective cough mechanism, and preserved postoperative lung volumes, including FRC and VC.²⁶ One study directly comparing epidural and general anesthesia in high-risk patients concluded that overall outcomes, including the need for prolonged postoperative ventilation, were improved with the regional technique.²⁷ Another trial in patients undergoing lower limb vascular surgery reported a greater than 50% reduction in the incidence of respiratory failure in the group randomized to epidural anesthesia.²⁸ A more recent metaanalysis of 141 randomized trials (including over 9000 patients) comparing regional and general anesthesia for hip surgery showed a risk reduction for pulmonary embolism, pneumonia, and respiratory depression of 55%, 39%, and 59%, respectively, with the regional anesthesia.²” Interestingly, these outcomes were unchanged regardless of whether neuraxial anesthesia was continued into the postoperative period, illustrating that the beneficial effect of epidural and spinal anesthesia on pulmonary physiology occurs, at least in part, at the time of surgical insult.

Brachial Plexus Block

In the absence of inadvertent complications such as pneumothorax, alterations in respiratory mechanics seen with brachial plexus block are due primarily to phrenic nerve blockade and hemidiaphragmatic paralysis. This has been shown to occur in 100% of patients receiving interscalene blockade,²⁹ and leads to a reduction by 27% in both FVC and FEVi.³⁰ While the clinical significance of this reduction in healthy patients is not entirely clear, it may be useful to risk- stratify patients about to undergo interscalene blocks as one would a patient undergoing lung resection. In other words, ask the question: “Will this patient tolerate a perioperative FEVi reduction of 27%?” Some investigators have attempted to reduce the incidence of phrenic nerve palsy by decreasing the volume of local anesthetic; however, volumes as little as 10-20 mL still result in diaphragmatic paralysis.^31,32 In fact, one case report illustrated clinically significant respiratory compromise requiring tracheal intubation following an interscalene block using a volume of 3 mL of 2% mepivacaine.³³

Clinical Pearls

        The risk of phrenic nerve blockade decreases as one moves more distally along the plexus. Axillary nerve block has no effect on diaphragm function and presents a good choice for those patients with marginal pulmonary reserve (ie, cannot tolerate a 27% reduction in lung function). On the other hand, the supraclavicular block is associated with a 50-67% incidence of hemidiaphragm paralysis.^34–36 The infraclavicular approach is probably sufficiently distant from the course of the phrenic nerve so as to spare the diaphragm,³⁷·³⁸ although there are case reports of phrenic nerve involvement.³⁹ These discrepancies probably relate to the different approaches to the infraclavicular block—for instance the “coracoid block” is performed with a relatively lateral or distal puncture site, whereas the vertical infraclavicular block begins at a more medial location. Although the infraclavicular or axillary blocks may be desirable for their relative pulmonary-sparing profiles, they carry the disadvantage of providing incomplete anesthesia for the upper arm and shoulder. However, creative solutions have been employed to get around this issue. Martinez and coworkers combined an infraclavicular block with a suprascapular nerve block for emergent humeral head surgery in a patient who was acutely asthmatic and had a baseline FEV] of 1.13 L (32% predicted). Therefore, a knowledgeable combination of peripheral nerve blocks can provide complete anesthesia of the upper limb while avoiding respiratory complications in patient with a pulmonary disease.⁴⁰

        Continuous brachial plexus blocks with perineural catheters are an attractive method of maintaining the advantages of plexus blockade into the postoperative period and have been shown to reduce postoperative pain, oral opioid requirements and their side effects, and sleep disturbances after shoulder surgery.⁴¹ However, there have been reports of complications attributed to the prolonged phrenic nerve paresis that invariably occurs with this technique. These have included chest pain, atelectasis, pleural effusion, and dyspnea.^42,43 This is of particular concern because many patients are being discharged home with catheters and may not have access to timely intervention should these complications arise. On the other hand, the degree of clinically significant respiratory impairment with continuous interscalene blockade varies among patients and, in fact, may be well tolerated, especially if using relatively dilute concentrations of local anesthetic that only provide a partial phrenic paresis.⁴⁴

Clinical Pearls

        Maurer and associates reported a case of a patient with no preexisting pulmonary disease who underwent bilateral shoulder arthroplasty under combined bilateral continuous interscalene blockade and general anesthesia.⁴⁵ Postoperative analgesia was maintained in the hospital for 72 h via the catheters using infusions of 7 mL/h of 0.2% ropivacaine for each side (total 14 mL/h). Despite a marked postoperative reduction in FVC (60%) from baseline as well as sonographic evidence of diaphragmatic impairment, the patient had an uneventful postoperative course (with excellent analgesia) and good recovery. This anecdotal example illustrates that the clinical significance of phrenic paresis in patients with good respiratory function is questionable. Regardless the use of continuous brachial plexus techniques should be carefully considered in patients with preexisting pulmonary disease, especially if they are to be discharged home with the catheters in situ.

Paravertebral & Intercostal Nerve Blocks

Several studies investigated the effects of paravertebral and intercostal blocks on pulmonary function in patients with rib fractures or those undergoing thoracotomy. Intercostal blockade has been shown to improve arterial oxygen saturation (Sao₂) and peak expiratory flow rate (PEFR) in patients with traumatic rib fractures associated with severe pain.⁴⁶ Likewise, Karmakar and investigators found that continuous paravertebral blockade over a period of 4 days in patients with multiple fractured ribs led to significant improvement in respiratory rate, FVC, PEFR, Sao₂, and the Pao₂ fraction of inspired oxygen ratio.⁴⁷ These findings are probably related to the favorable effect of analgesia on respiratory efforts by the patient and improved respiratory mechanics.

        Paravertebral blocks are very effective for management of pain following thoracotomy and can significantly improve postoperative spirometry One review of 55 randomized, controlled trials of analgesic techniques following posterolateral thoracotomy revealed that paravertebral blockade was the method that best preserved pulmonary function compared with either intercostal or epidural analgesia.⁴⁸ The combined results showed an average preservation of approximately 75% of preoperative pulmonary function when paravertebral analgesia was used versus 55% for both intercostal and epidural analgesia. It is unclear why paravertebral blockade might result in improved PEFR and Sao2 compared with epidural analgesia in this and other studies, but it may be related to increased utilization of opioids, higher incidence of nausea and vomiting, and the presence of bilateral intercostal muscle blockade (and therefore diminished chest wall mobility) in the epidural cohorts.⁴⁹

Clinical Pearls

Pulmonary Complications Not Related to Conduction Blockade

Pulmonary complications related to the use of regional anesthetic techniques fall into two categories. The first is those related directly or indirectly to the physiologic changes that occur with the blockade itself. Examples include atelectasis and pneumonia resulting from an inability to mobilize secretions. The second category comprises those that are independent of the effect of blockade, and although there are sporadic reports of rare complications such as pulmonary hemorrhage⁵⁰ and chylothorax,⁵¹ the most common of these is pneumothorax. Not surprisingly, pneumothoraces occur most frequently when the puncture site overlies the pleura, and especially when performing supraclavicular and intercostal blocks. The overall incidence is low, however,^52–55 and refinements of previously published techniques based on MRI studies and ultrasound guidance can decrease the incidence further.^56,57 Nevertheless, techniques with a risk of pneumothorax should be carefully considered or avoided in patients with borderline pulmonary function.

        RENAL DISEASE

Renal dysfunction is commonly present in the surgical population. Perioperative renal failure accounts for approximately 50% of all patients requiring acute hemodialysis in the United States. Patients with chronic renal insufficiency frequently present for procedures, such as creation of vascular shunts and revascularization of the lower limbs. Regional anesthetic techniques are frequently ideal options to provide anesthesia for these patients and procedures.

Effect of Regional Anesthesia on Renal Function

The treatment of patients at risk for perioperative renal dysfunction should focus on two principles: avoiding nephrotoxic agents and maintaining kidney perfusion. Local anesthetics do not possess any nephrotoxic properties per se, and in fact the coadministration of procaine has been shown to mitigate some of the nephrotoxic effects of cisplatin in rats.⁵⁸ Of greater relevance is the effect of anesthetic-induced hypotension on renal blood flow. The kidneys are capable of autoregulation over a wide variety of mean arterial pressures (approximately 80-180 mm Hg) and maintain glomerular filtration rate (GFR) by autonomous changes in renal vascular resistance.⁵⁹ Below the so-called lower limit of autoregulation, the kidney begins to shut down its energy-dependent physiologic processes, and the GFR and urinary output fall as a result. Ultimately, if left unchecked, renal ischemia develops, especially in the sensitive renal medulla. Although neuraxial anesthesia and the concurrent sympathectomy can reduce mean arterial pressure (MAP), renal blood flow is often preserved.⁶⁰ This is believed to reflect an increase in left ventricular stroke volume in response to the drop in systemic vascular resistance (SVR). Rooke and investigators studied hemodynamic responses and abdominal organ perfusion (as measured by scintigraphy) in 15 patients undergoing lidocaine spinal anesthesia with a sensory block ranging from Tl to T10.⁶¹ Whereas the MAP and SVR fell on average by 33% and 26%, respectively, blood volume in the kidneys increased by approximately 10%. There may be limits to the degree of compensation afforded by cardiac output, however. One study using a primate model showed that although renal blood flow was minimally affected by T10 spinal anesthesia, it was significantly reduced by a Tl sensory block.⁶² This illustrates again that lumbar and low thoracic levels of neuraxial anesthesia in patients with renal disease are well tolerated physiologically and significant changes do not begin to manifest until higher levels are achieved.

Clinical Pearls

        The renin-angiotensin system, which is initiated in the kidney in response to a reduction in renal perfusion, plays an important role in blood pressure homeostasis. It serves as a complementary humoral mechanism to the sympathetic nervous systems. Hopf and colleagues conducted a study to determine if thoracic epidural anesthesia suppressed the renin response to induced hypotension.⁶³ Plasma renin and vasopressin concentrations were measured before, during, and after a hypotensive challenge with nitroprusside in patients with and without thoracic epidural anesthesia (sensory level Tl through Til). With an intact sympathetic nervous system (ie, no epidural), plasma renin levels doubled in response to the hypotensive challenge lasting 15 min. In contrast, there was no change in the renin concentration when hypotension was induced to the same MAP in the epidural cohort. This suggests that sympathetic fibers play a key role in the renin-angiotensin system and that thoracic epidural anesthesia interferes with the functional integrity of that system.

        For obvious reasons, postoperative renal function is of foremost concern when administering anesthesia for recipients of renal transplantation. Several studies have looked at the effect of general versus regional (or combined epidural/general) anesthesia on postoperative renal function in this setting. The choice of anesthetic technique was not shown to have an effect on graft outcome in either adult or pediatric populations.^64,65 Also, the choice of anesthetic technique for living donors was shown to be independent of recipient graft outcome.⁶⁶ Other nontransplant outcomes data, including those from the large meta-analysis by Rodgers and coworkers, indicate that regional anesthesia is associated with a lower risk for postoperative renal failure than general anesthesia. However, the authors cautioned that the confidence intervals were wide and were compatible with both no effect and a two-thirds risk reduction.²⁵ Overall, it appears that a well- conducted regional anesthetic does not negatively affect perioperative kidney function and renal outcome compared with general anesthesia.

Considerations for Regional Anesthesia in Chronic Renal Failure

Patients with chronic renal failure often manifest a large number of pathophysiologic changes that may influence regional anesthetic care. These may include the presence of an anion-gap metabolic acidosis, electrolyte disturbances such as hyperkalemia, and coagulopathies due to uremia-induced platelet dysfunction. Plasma concentrations of local anesthetic following peripheral nerve blocks are often high enough to cause central nervous system or cardiac toxicity in any patient, even when no obvious intravascular injection has occurred. This is probably related to the large dose used when performing “high-volume blocks” such as brachial plexus blocks. Some authors have recommended that dosages be adjusted in patients with chronic renal insufficiency based on observations of toxicity presumed to be related to concurrent acidosis or hyperkalemia.^67,68 Indeed, experimental evidence suggests that acidemia decreases the protein binding of bupivacaine, thereby increasing the free fraction and risk of toxicity.⁶⁹ In addition, hyperkalemia (5.4 vs 2.7 mEq/L) has been shown in dogs to halve the dose of bupivacaine required to induce cardiotoxicity.⁷⁰ Interestingly, the potassium level had no effect on seizure dose in the same animals. This is an ominous finding, as it suggests that the so-called safety margin of plasma levels between CNS and cardiac toxicity, which is already relatively narrow with bupivacaine, is even less reliable in the presence of hyperkalemia. Even in the absence of acid-base or electrolyte disturbances, plasma levels of local anesthetics following peripheral nerve block are often higher in patients with chronic renal failure.^71,72 The reason for this is not entirely clear, but may relate to increased blood flow (and hence uptake at the injection site) due to the hyperdynamic circulation often seen in uremic patients.⁷³ On the other hand, �i-acid glycoprotein (AAG) levels are increased in uremia⁷⁴ and may lend a protective effect by binding more local anesthetic in the bloodstream.⁷⁵ The increased levels of AAG also result in both a reduced free fraction available for hepatic metabolism and in a reduced volume of distribution. These two pharmacokinetic consequences appear to balance each other so that the serum half-life is not significantly changed.⁷¹ Hemodialysis is ineffective in removing lidocaine from plasma, and therefore cannot be relied on to treat toxicity.⁷⁶

Clinical Pearls

        No significant difference exists between patients with chronic renal failure and healthy patients with respect to peripheral nerve block latency, duration, or quality.^71,77,78 In one study of spinal anesthesia properties in patients with chronic renal failure versus healthy patients, Orko and associates found that block quality was similar, but that both onset time and duration of the block were reduced in the patients with uremia.⁷⁹ The authors postulated a volume-contracted intrathecal space in uremic patients as a mechanism for the quicker onset, but the actual cause remains speculative. The shorter duration of sensory block may again be related to enhanced uptake in the setting of a hyperdynamic circulation.

        Uremic coagulopathy is characterized by a defect of platelet aggregation that is probably due to a toxic effect by uremic substances on the binding of fibrinogen to the platelet glycoprotein Ilb/IIIa receptor.⁸⁰ This often manifests in clinically appreciable bleeding, and at least one case of subarachnoid hematoma leading to paraplegia after a spinal anesthetic in a chronic renal failure patient has been published.⁸¹ Patients undergoing hemodialysis require intermittent anticoagulation and may present to the operating room with an unclear coagulation status. Care must be taken to delineate heparin or other anticoagulant regimens. Despite this platelet dysfunction, uremic patients are at higher risk for thrombotic events.⁸² One case of hypoxia following a brachial plexus block in a uremic patient was later found to be secondary to pulmonary embolism.⁸³ The authors of the report suggested that a likely mechanism was dislodgement of a preexisting thrombus from the proximal arm, facilitated by block-related manipulation and vasodilation of the upper extremity.

        Several studies have compared anesthetic techniques for the creation of arteriovenous fistulae, a procedure that is common in patients with end-stage renal disease and is well suited to brachial plexus block.⁸⁴ Although some investigators have concluded that little difference exists in outcome between general, local, and brachial plexus anesthesia for this operation,⁸⁵ Mouquet and colleagues specifically studied the effects of these three techniques on brachial artery blood flow and concluded that both general anesthesia and brachial plexus block improved blood flow through the fistula during surgery, whereas local infiltration did not.⁸⁶

        HEPATIC DISEASE

Liver injury or dysfunction can range from a mild, asymptomatic “transaminitis” to frank hepatic failure. There are many causes of liver disease, both acquired and congenital, but all manifest as either failure of parenchymal cell function (ie, acute and chronic hepatitis, cirrhosis) or cholestasis.⁸⁷ Considerations for regional anesthesia in patients with liver disease include the potential for altered disposition and metabolism of local anesthetics, the effect of regional anesthesia on hepatic perfusion, and concerns regarding coagulopathy related to liver dysfunction.

Pharmacokinetics of Local Anesthetics in Liver Disease

Amide local anesthetics are metabolized in liver microsomes by the cytochrome P-450 system.⁸⁸ A decrease in microsomal function, as may be seen in acute or chronic liver disease, can lead to a reduction in biotransformation and clearance of these drugs, putting the patient at risk for local anesthetic toxicity. As with other drugs that are metabolized in the liver, the hepatic extraction ratio determines the relative importance of hepatic perfusion versus intrinsic enzyme activity in the overall clearance of the drug. For example, bupivacaine has a low extraction ratio (ie, its clearance is more sensitive to alterations in hepatic enzyme activity), whereas etidocaine exhibits a relatively high extraction ratio and depends on adequate liver perfusion for clearance.⁸⁹ Lidocaine has an intermediate hepatic extraction ratio and therefore relies on both perfusion and enzymatic activity. Severe hepatic disease such as cirrhosis can affect both liver perfusion and intrinsic enzyme function. In this scenario, the clearance of all amide local anesthetics, regardless of their extraction ratio, is likely to be reduced. Because the volume of distribution of local anesthetics (and many other drugs) is increased in hepatic disease, the actual plasma levels may not differ significantly from healthy patients with a single dose, despite the diminished clearance.^90–92 The altered distribution may be related to decreased levels of plasma AAG, which are reduced in proportion to the severity of liver disease.⁹³ Clinically, it appears that single-dose peripheral nerve blocks with amide local anesthetics probably do not require a dosage adjustment in this population, whereas continuous infusions have the potential to accumulate to toxic levels.⁹⁴

Clinical Pearls

Related posts:

Regional Anesthesia in the Patient with Preexisting Neurologic Disease. The History of Local Anesthesia. Stimulating Catheters. Ultrasound-Assisted Nerve Blocks in Adults. Cutaneous Blocks for the Upper Extremity. Cervical Plexus Block.