Amyloidosis and Anesthesia.

AIM: The aim of this article is to provide a view of amyloidosis and discuss implications for the anesthetic management of patients with this condition. MATERIAL AND
METHOD: Urine samples from patients with plasma cell dyscrasias were obtained from a urine bank that gathers urine samples from patients who gave research use consent for specimens that would otherwise be considered waste.
RESULTS: Patients with amyloidosis may present to the anesthesiologist for procedures relating to diagnosis, surgery relating to the underlying condition (e.g., bronchial laser and organ transplant), or for incidental surgery. The condition carries a significant risk of perioperative morbidity and mortality.
CONCLUSION: The term amyloid was coined by Virchow in the mid 19th century, meaning "starch like." Amyloidosis is a disease complex, in which there is an abnormal deposition of extracellular hyaline material with particular staining characteristics and which contains protein fibrils embedded in a relatively amorphous ground substance. There are numerous clinical manifestations, the onset is insidious, and the diagnosis may not be made in a patient undergoing anesthesia and surgery for an apparently straightforward problem. Unexpected complications such as heart or kidney failure may arise, either before operation or in the postoperative period. Bullous lesions of the skin or oral mucosa and extensive areas of purpura are but two of the ways, in which amyloidosis may first present. The disease spectrum may be inherited or acquired, localized or systemic, and life threatening or an incidental finding.

INTRODUCTION

Amyloidosis is a heterogeneous disease or even considered a constellation of diseases resulting in a deposition of relatively similar proteins. Amyloid is an insoluble extracellular proteinaceous substance composed of cross-ß-pleated sheets which have the property of apple-green birefringence when viewed under polarized light.[1] It has many causes and can affect essentially any organ system. Amyloidosis is such a complex and progressive disease that its treatment options vary depending on the type of amyloidosis present and extent of organ involved. Amyloidosis has multiple implications for anesthesia providers due to the possibility of multiorgan involvement. A pink–red coloration is seen with the Congo red stain. Patients with amyloidosis are seen in the operating rooms for diagnostic, interventional, and curative purposes. Anesthesia providers must be aware of the multisystem involvement of amyloidosis and the related anesthetic implications. Each amyloidosis case is unique, and the anesthetic must be determined on a case-by-case basis and tailored to the individual signs and symptoms; the patient is experiencing. No one knows what causes amyloidosis. There may be more than one cause. Hereditary amyloidosis results from genetic changes that cause the body to make abnormal proteins. As we get older, damage builds up in the body and triggers the disease. This kind of damage may come from the body's use of oxygen (oxidation) and from free radicals (harmful by-products formed when cells use energy). Once amyloid deposits start, they seem to continue building up in the same locations. The heart, kidneys, nervous system, and gastrointestinal (GI) tract are the most commonly affected. The amyloidoses constitute a heterogenous group of diseases that share the pathogenic feature of protein misfolding. Precursor proteins, produced by various mechanisms, are deposited extracellularly as insoluble fibrils resulting in disruption of tissue architecture and organ dysfunction. There is evidence that some proteins may have their own toxicities independent of the effects from deposition. Clinical manifestations depend on the specific precursor protein, the pattern of tissue distribution, and the extent of infiltration. Inherited and acquired factors are implicated in the etiology although the exact trigger is unknown. Amyloidosis may occur as its own entity or in association with other disease states, such as dialysis-dependent renal failure, malignancy, chronic infection, and inflammation.

Systems Involvement

Airway and the respiratory tract

The head and neck region is a comparatively frequent site for deposition although localized amyloid may affect both the upper and lower respiratory tract [Figure 1]. Patients present for diagnostic (e.g., microlaryngoscopy and biopsy) and treatment purposes (e.g., laser therapy, surgical resection, and airway stenting) or in the emergency setting for the management of a threatened airway. Macroglossia is a highly characteristic feature, occurring in ~20% of the patients [Figure 2]. Deposits in mesenchymal tissue lead to a large, poorly mobile tongue and predispose to difficult intubation. Laryngeal amyloid represents ~1% of benign laryngeal disease, with male predilection and incidence increasing with age. Presentation is usually with progressive hoarsiness – because of loss of vocal cords tone and paralysis of surrounding muscles [Figure 2]. Dyspnea, cough, stridor, and odynophagia may also be apparent [Figure 3].

Figure 1

Lower airway involvement (a) Normal airway (b and c) Amyloidosis affected airway.

Figure 2

A patient with amyloidosis showing thickening of the skin of the perioral and muzzle region of the face and tongue.

Figure 3

Affect of amyloidosis on vocal cords (a) Normal vocal cords (b) Amyloidosis affected vocal cords.

Cardiovascular system

Infiltration of myocardium leads to a decline in cardiac performance [Figure 4]. Restrictive cardiomyopathy, diastolic heart failure, conduction disorders, and ischemic heart disease may ensue. Progressive heart failure and fatal cardiac arrhythmias in the perioperative period have been reported.[234]

Figure 4

Echocardiographic apical four-chamber view from a patient with Amyloid light-chain (AL) amyloidosis. Both ventricles are thick walled with an increased echogenicity (sometimes referred to as granular sparkling or scintillation pattern) with nondilated cavity size. The atrioventricular valve leaflets are thickened, and there is significant biatrial dilatation.

As disease advances, resting arterial pressure decreases due to reductions in cardiac output and systemic vascular resistance. Orthostatic hypotension may be compounded by autonomic or endocrine dysfunction.

Hematological

Bleeding tendency includes microvascular fragility, platelet dysfunction, and impaired fibrin formation, in addition to qualitative and quantitative clotting factor deficiencies. Acquired factor X deficiency is the most common, occurring in approximately a third of patients. Isolated deficiencies of factors II, V, VII, and IX are also reported. In other forms of amyloid, infiltration-induced microvascular fragility and impaired vasoconstriction are considered the primary causes of abnormal bleeding. Vessel fragility has been proposed to account for hemorrhagic rashes in response to minimal trauma at sites of electrocardiogram (ECG) electrode placement[5] and purpura complicating the use of adhesive tape for eye protection[6] and tracheal tube placement.[7]

Neurological system

Autonomic and peripheral neuropathy is seen along with postural hypotension and carpal tunnel syndrome.

Other systems

Renal involvement presents with nonspecific proteinuria, nephrotic syndrome, or renal insufficiency

GI manifestations of amyloid include visceral organomegaly, early satiety, malabsorption, protein-losing enteropathy, ascites, dysmotility, and GI hemorrhage. Substantial variation of symptoms occurs. Deranged liver function may result primarily from infiltration of amyloid proteins, secondary to congestive cardiac dysfunction, or a combination of both.

PHARMACOLOGICAL CONSIDERATIONS

The choice of technique is determined by the patient's condition, the nature of surgery, and the individual expertise of the anesthetist. Pharmacokinetics and pharmacodynamics vary depending on the pattern and degree of organ dysfunction. Pharmacological interactions may also occur, such as anticholinesterases used in Alzheimer's disease producing a prolonged response to succinylcholine.

The important anesthetic drug considerations with relevance to amyloid are summarized in Table 1.

Table 1

The important anesthetic drug considerations with relevance to amyloid are summarized

PERIOPERATIVE MANAGEMENT

Preoperative assessment

The patient with amyloidosis should be approached with caution. Variable disease manifestations mean that individual patients require meticulous assessment and a tailored anesthetic plan. Preoperative evaluation and optimization by specialists in cardiology, neurology, nephrology, and hematology may be appropriate, depending on organ involvement. Given the insidious nature of the disease, the possibility of amyloid should be considered in patients with unexplained nonspecific symptoms suggesting multisystem involvement.

For elective surgery, directed medical optimization by cardiology specialists is warranted. Such preparation is impractical in the emergency scenario, where cardiac dysfunction should be presumed and a “cardiostable” plan formulated. This may influence the anesthetic technique (regional vs. general), the choice of pharmacological agents used, and the surgical approach (laparoscopic vs. open).

Detailed airway assessment is essential. Macroglossia is almost pathognomonic of systemic AL and suggests difficulties in airway management. Esophageal dysmotility, if present, may warrant rapid sequence induction of general anesthesia. A targeted work-up for the head, neck, and chest pathology may include plain chest radiographs, pulmonary function tests, nasendoscopy, and computerized tomography scanning.

Investigations should be tailored to the patient's condition and the intended surgery. Full blood count, urea and electrolytes, liver function tests, coagulation profile, and an ECG may be considered a minimum requirement. Tests of coagulation and platelet function should be performed before procedures although normal results do not exclude clinically significant bleeding. This may be especially important where neuraxial blockade is contemplated. Detailed hematological work-up allows targeted prophylaxis or therapy in the perioperative setting. Optimization of fluid status, hemoglobin, and serum electrolyte profile should be ensured before operation to minimize the risk of cardiac arrhythmias. The ECG in amyloidosis is associated with low-voltage QRS complexes, conduction abnormalities, and pseudoinfarction patterns [Figure 5]. Holter monitoring may reveal atrial and ventricular arrhythmias. Implantable cardioverter defibrillator insertion may be desirable before elective surgery to reduce risk from malignant arrhythmias. Echocardiography is important for confirming cardiac involvement, estimating prognosis, and directing the conduct of anesthesia.

Figure 5

A 12-lead electrocardiogram from a patient with AL amyloid heart involvement. There is extreme low voltage in the limb leads (all < 0.5 mV) with a pseudoinfarction pattern in the anterior leads (Q/S waves from V1 to V3). Note that despite obvious cardiac involvement, the patient remains in sinus rhythm.

The importance of nutrition on patient outcome is well recognized in critical care. In patients with evidence of malnutrition, adequate supplemental nutrition should be ensured in the perioperative period.

Where endocrine involvement is suspected, tests of endocrine function (e.g., thyroid, cortisol, and synacthen) are appropriate. Steroid supplementation may also be required depending on the dose and duration of preoperative steroid use.

The risks conferred by proceeding with surgery must be balanced against intended benefits at the consent stage. Where appropriate, limits of treatment should also be addressed. Patients with central nervous system amyloid (e.g., Alzheimer's dementia) may lack the capacity to provide informed consent. In such circumstances, a family member, carer, or mental capacity advocate should be involved.

Sedative premedication may be administered as appropriate where close monitoring for hypoxemia and respiratory depression is available.

INTRAOPERATIVE

Monitoring depends on the patient and nature of surgery. The risk of cardiac complications from anesthesia, surgical stress, and bleeding necessitates close monitoring. Specific aims are the maintenance of sinus rhythm and optimization of contractility, heart rate, preload, and afterload. Vasopressor or inotropic infusions may be required to support organ perfusion. Invasive arterial and central venous pressure monitoring allows improved hemodynamic control and interval blood sampling. In patients taking midodrine, vasopressor requirements may be reduced or absent. Instances of supine hypertension may respond to simple measures such as reverse Trendelenburg positioning and deepening anesthesia.

Cardiac performance may be monitored invasively (e.g., pulse contour analysis and pulmonary artery catheters) or noninvasively (e.g., echocardiography and Doppler methods). Directly measured and derived hemodynamic data allow titration of vasopressor and inotropic support. Cardiac arrhythmias should be identified and treated promptly. Detection of arrhythmias and myocardial ischemia may be assisted through CM-5 lead monitoring. Depth of anesthesia monitors provides the dual advantages of reducing the risk of awareness and excessive anesthetic depth.

Inadvertent perioperative hypothermia is associated with adverse outcomes (e.g., morbid cardiac events and coagulopathy). Temperature monitoring linked to the use of ambient theater temperature control, heat/moisture exchangers, forced air, and fluid warmers should be used to ensure normothermia.

Near-patient tests of coagulation allow rapid detection and focused treatment of problematic bleeding. This may include blood products (e.g., fresh frozen plasma, cryoprecipitate, fibrinogen, platelets, and coagulation factor concentrates) or pharmaceutical agents (e.g., antifibrinolytics and vasopressin analogs). Cell salvage may be utilized to compensate for significant bleeding and reduce transfusion requirements.

Careful patient handling, pressure point care, the use of alternatives to adhesive tape, and avoidance of high inflation pressures may reduce amyloid-associated bleeding risk.

Regional techniques should be considered, alone or in combination with sedation or general anesthesia. When used alone, regional blockade can obviate risks associated with airway management. Other potential advantages include superior analgesia, attenuation of the stress response, and avoidance of polypharmacy. The potential for amyloid-associated bleeding should be considered alongside standard risks of regional blockade.

POSTOPERATIVE

Supplemental oxygen administration should be provided. Postoperative complications relate to amyloid type, other comorbidities, or the surgery undertaken and are interdependent (e.g., fluid and electrolyte shifts in major GI surgery). Emerging issues (e.g., pain, bleeding, and infection) should be identified and managed effectively to reduce the likelihood of organ decompensation. If the patient is considered unstable, admission to an intensive care or high dependency unit should be arranged. When suitable for ward transfer, detailed discharge planning and ongoing close observation are required, even if the patient is apparently problem free. Multidisciplinary involvement throughout the perioperative period is essential to optimize treatment.

CONCLUSION

Amyloidosis, first described in 1853 by Virchow, is now classified as one of the beta-fibrilloses due to characteristic fibrillar component which has a beta-pleated sheet configuration. It is regarded as the most important cause of human illness than had previously been appreciated.

Amyloidosis mimics many common disorders, but if doubt exists, the diagnosis may generally be made quite simple by rectal or skin biopsy.[8]

Survival is often <2 years. Some success has been achieved with various cytotoxic drugs, corticosteroids, and colchicines, and renal transplantation has been performed in case of renal failure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.