Systemic Lupus Erythematosus
Fever in the patient with lupus presses the clinician for an urgent answer to the question: Is this caused by lupus activity or infection? Fever is a common finding in active systemic lupus erythematosus (SLE) and follows no specific curve or pattern.2 It may respond to the usual antipyretics or require corticosteroids. Single-daily-morning dose prednisone may not control late afternoon or evening fevers. Leukocytosis and increased bands on peripheral smear are strong presumptive evidence for infection, as is the presence of shaking chills. Complement proteins or components, including C3 and C4, are acute-phase reactants and usually rise with infection. Low levels of complement occur in some but not all patients with active lupus. Using discriminant analysis, Inone and colleagues3 showed that 95% of 74 febrile episodes could be correctly classified as to the cause of fever when a combination of white blood count (low in SLE, normal to high with infection) and α2-globulin levels (high with SLE, normal with infection) are used as variables.
In the ICU setting, the febrile patient with SLE is probably best considered infected and treated with broad-spectrum antibiotics pending results of cultures.4 Infection is most likely to be caused by nonopportunistic organisms, and coverage for gram-positive and gram-negative aerobes represents adequate empirical therapy when no obvious source has been recognized. Systemic infections with Salmonella, endocarditis involving lupus-related valvular lesions, and pneumococcal sepsis in the splenectomized (surgical or autosplenectomy) are among the infections that have special significance for lupus patients.
Myocardial Infarct in the Lupus Patient: Is It Vasculitis?
Myocardial infarction makes a major contribution to excessive mortality in SLE. Mortality data suggest a bimodal distribution with many late deaths in SLE secondary to ischemic heart disease. The primary cause of ischemic heart disease in lupus is atherosclerosis. Autopsy studies in young women with lupus with death from any cause show an excessive incidence of atherosclerosis in comparison to age-matched females.5 The cause of accelerated atheroma is not totally clear, but inflammation of the vascular endothelium due to chronic immune complex disease compounded by the effects of corticosteroids probably is the major contributing factor.
Vasculitis in SLE may affect any organ including the heart. Most patients with coronary artery vasculitis have evidence of vasculitis in other organs. Serologic evidence of active lupus and markers of systemic inflammation including low hemoglobin and albumin are likely to be present. Acute therapy would include high-dose corticosteroids (see below). In the face of widespread vasculitis, additional intervention with parenteral immunosuppressives, B-cell–depleting biopharmaceuticals, and plasmapheresis may be indicated.
Another potential cause of myocardial ischemia is coronary thrombosis secondary to antiphospholipid syndrome.6 Treatment is anticoagulation with heparin. Thrombolytic therapy has been successfully used in some patients with antiphospholipid syndrome.7
Corticosteroids are potentially hazardous, and high doses may predispose to ventricular rupture. Therefore corticosteroids should not be used in the absence of reasonable clinical suspicion for coronary vasculitis. If the lupus patient is in apparent clinical remission without evidence of widespread vasculitis, treatment should be the same as that for the non-lupus patient. Early cardiac catheterization may help clarify the nature of the vascular disease.
Renal Failure: Is It Treatable Lupus Nephritis?
In patients with SLE in the ICU, renal insufficiency may be caused by a variety of factors, including drugs, especially nonsteroidal anti-inflammatory drugs (NSAIDs), hypovolemia, sepsis, or previous renal disease.8 In some cases, active lupus nephritis is a contributing factor. A careful examination of the urinary sediment is the most critical diagnostic tool. Proteinuria, casts, and red blood cells indicate glomerulitis. Lupus patients with active nephritis are most often hypertensive. Significant renal lupus (other than membranous disease) is often associated with low complement levels and elevation of anti-DNA antibody.
In a patient with a creatinine level above 4.0 mg/dL who has been adequately hydrated, has been divorced from nephrotoxic drugs, and shows evidence of active glomerulitis, the question arises: Is more aggressive immunosuppression desirable? The answer to this question depends on the degree of potential disease reversibility. A renal biopsy can help clarify this issue. The presence of significant chronic disease should dampen enthusiasm for aggressive therapy. Review of old records can be enlightening if long-standing loss of renal function is documented.
Clinicians have become increasingly aware that immunosuppression in the lupus patient with advanced renal disease can be more hazardous than progression to complete renal failure. Patients with lupus tolerate dialysis in a fashion comparable to other patients, and results of renal transplantation are favorable.9 Paradoxically, patients with lupus who develop chronic renal failure often enjoy an amelioration of extrarenal symptoms.10 A few patients have recovered sufficient renal function to allow withdrawal from dialysis. For all these reasons, the overzealous administration of immunosuppression in patients with lupus and advanced renal disease is to be discouraged.
Respiratory Failure and Lung Infiltrates: Is It Lupus Pneumonitis?
Respiratory failure in the patient with SLE is an ominous development. A paradigm of a compromised host is a patient with lupus who is on high-dose corticosteroid therapy. The usual opportunistic pulmonary infections need to be urgently excluded by bronchoalveolar lavage, bronchoscopic transbronchial biopsy, or open lung biopsy. If no superimposed infections or embolic etiology can be found and treated, lupus-related respiratory failure remains a diagnosis of exclusion and can be caused by either lupus pneumonitis or diffuse pulmonary hemorrhage. Acute lupus pneumonitis may occur as an initial manifestation of SLE and is characterized by fever, tachypnea, and hypoxemia, which may be accompanied by cough, pleuritic chest pain, and hemoptysis.11 Radiologic findings are highly variable but usually bilateral and at least bibasilar. This diagnosis is not only one of exclusion; it unfortunately still rests solely on clinical suspicion.
The other SLE-related cause of respiratory failure is diffuse alveolar pulmonary hemorrhage.12 Although invasive Aspergillus or tuberculosis can erode a pulmonary vessel and cause hemorrhage, gross hemoptysis, when present, usually indicates alveolar hemorrhage. Hemoptysis is not usually seen in lupus pneumonitis; unfortunately, this finding is present in <50% of patients with alveolar hemorrhage. Blood or hemosiderin-laden macrophages found during bronchoscopy in a patient without heart failure can be helpful findings but are nonspecific. The presence of thrombocytopenia is not helpful, but bleeding sufficient to cause acute respiratory failure most invariably causes an acute drop in hematocrit. In fact, treatment should not be delayed in order to distinguish between lupus pneumonitis and lupus-associated hemorrhage, because mortality is extremely high in either syndrome and treatment strategies are similar.
Pulmonary hypertension, sometimes severe, is frequently present. Cardiac filling pressures, in contrast to B-type natriuretic peptide determinations, can occasionally be helpful discriminators to exclude acute cardiogenic pulmonary edema. Pulmonary artery thrombosis masquerading as massive pulmonary emboli can occur in patients with pulmonary hypertension or thrombotically active anticardiolipin (ACL) antibodies.
The mortality of lupus pneumonitis is high, and treatment should be aggressive. Individual preferences will dictate modes of therapy, since no consensus exists on either the etiology of the syndrome or effective treatment. Pulse methylprednisolone, usually 500 to 1000 mg intravenously given for 3 to 5 days, or bolus cyclophosphamide at 0.5 to 1.0 g/m2 has been used. Uncontrolled studies of plasmapheresis for alveolar hemorrhage in SLE do not reveal striking therapeutic efficacy. In the absence of alternate therapy with proven effect, plasmapheresis may be useful as a temporizing measure during the induction period required for the optimal effects of immunosuppressive agents like cyclophosphamide.13
Brain Dysfunction: Is It Lupus?
A patient with acute, severe neurologic deficits and a history of SLE or a clinical syndrome and laboratory evidence suggestive of systemic vasculitis presents a diagnostic and therapeutic dilemma for the critical care clinician. In the vast majority of instances, involvement of the central nervous system (CNS) in SLE occurs as an organic brain syndrome or seizures in young females with active multisystem disease. Patients with organic brain syndromes manifest psychosis usually early after the onset of SLE. A common dilemma is to differentiate between steroid-induced pseudo-organic brain syndromes and those owing to active SLE. Interleukin-6 (IL-6) levels are markedly increased in the CSF of patients with active CNS SLE. Minimal, if any, IL-6 should be present in the CSF of patients with steroid-induced psychosis, and IL-6 may prove very helpful in differentiating between drug-induced CNS changes and active SLE. Early-onset development of psychosis while on low doses of corticosteroids and fulminant progression usually characterize the CNS disease caused by SLE.14 Depressive syndromes with or without auditory, visual, or even olfactory hallucinations in a patient on a dose of corticosteroids usually higher than 0.5 mg/kg per day are usually drug-induced. Because there is little evidence that high-dose corticosteroids ameliorate the CNS manifestations of SLE, rapid reduction of corticosteroid dosage is usually the simplest and most direct clinical strategy when a quandary exists as to whether CNS dysfunction is drug-induced.
Lupus-induced seizures are usually grand mal but can be very pleomorphic and usually occur in patients with active SLE.15 Rapidly progressive, multisystem SLE that is further complicated by early onset of a seizure syndrome usually portends a poor outcome. The development of a seizure disorder in a patient with a long history of inactive SLE or in a patient with SLE entering remission is usually caused by something else. There is also little clinical evidence that high-dose corticosteroids alone influence the course of seizure disorders in SLE, and these patients should be aggressively treated with conventional anticonvulsive therapy. A difficult but critical differentiation must be made in SLE patients with CNS findings, anemia, and thrombocytopenia. The latter findings, while very common in active SLE, coupled with peripheral blood smear evidence of microangiopathy, point instead to thrombotic thrombocytopenic purpura (TTP) (see Chap. 70). Case reports suggest that TTP and SLE can co-occur, and the differentiation between the two diseases is vital since the treatment of life-threatening TTP is plasma exchange and not concomitant pulse methlyprednisone, alkylating agents, and/or plasmapheresis that many rheumatologists, in spite of unproven benefit, will resort to in the setting of fulminant CNS SLE.
Three other CNS manifestations of SLE can be puzzling. A small subset of patients with SLE who have taken NSAIDs, especially ibuprofen, will develop a meningitis-like picture that is characterized by fever, severe headache, nuchal rigidity, and cerebrospinal fluid neutrophilia or pleocytosis.16 In an immunosuppressed patient, these findings prompt consideration of both common and unusual bacterial and fungal etiologies. The entire syndrome will remit rapidly once the drug is discontinued.
Migraine headaches, some of spectacular intensity, are frequent in SLE.17 They usually respond to increases in corticosteroid dosage.
Actual paralysis is uncommon in SLE. Rare instances of transverse myelitis occur in the context of active SLE, and myelopathy may rarely be the presenting symptom of lupus. Until recently this was thought to be secondary to necrotizing vasculitis in the spinal arteries. It is likely, however, that many instances have been secondary to thrombosis associated with high titers of IgG ACL antibodies.18 This differentiation may be important because the primary treatment of this syndrome is not aggressive immunomodulation of SLE, but appropriate anticoagulation.
Some investigators have reported elevated serum levels of anti-ribosomal P antibodies in patients with lupus-induced depression or psychosis. Other studies have not confirmed the association of these antibodies with psychosis.
The emergence of effective therapeutic options has given the detection of pulmonary vascular disease a new sense of urgency. The exact prevalence of pulmonary hypertension in scleroderma is unknown. Hospital-based studies would suggest the number to be in the 10% to 15% range.19 There are generally two settings in which it is identified. In patients with limited cutaneous systemic sclerosis (calcinosis, Raynaud's phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia [CREST] variant of scleroderma) it occurs classically as an isolated phenomenon in the absence of pulmonary fibrosis. This generally occurs in the second decade of disease or later. Patients who fall into the second major category of scleroderma, diffuse disease, may develop pulmonary hypertension as the result of advanced pulmonary fibrosis. In both settings the vascular disease is characterized by bland endothelial proliferation and vascular occlusion. The vasculopathy of scleroderma is not characterized by an inflammatory infiltrate and is not treated with corticosteroids or immunosuppression in the manner that typifies the treatment of lupus vasculitis.
Early symptoms of pulmonary hypertension are exertional breathlessness, but later symptoms are likely to provoke admission to the medical ICU or critical care unit (CCU). These include near-syncope or syncope with exertion and right ventricular angina or heart failure. Scleroderma patients, especially those at greatest risk for pulmonary hypertension, are now screened yearly or every few years using Doppler echocardiography. Confirmation of diagnosis demands a right heart catheterization, which provides additional important information about pulmonary capillary wedge pressure and cardiac output.
The treatment of pulmonary hypertension in the context of scleroderma is similar to that in idiopathic and familial pulmonary hypertension.20 Anticoagulation, diuretics, digoxin, and supplemental oxygen form the basic management program. A small subset of patients may benefit from calcium channel blockers. Two exciting breakthroughs have substantially changed the quality of life of these patients for the better. Parenteral epoprostenol was initially viewed as a bridge to transplant, but some patients have elected to continue the drug as a chronic maintenance therapy. The emergence of a broad-spectrum endothelin receptor antagonist in the form of bosentan now offers the option of oral therapy to patients with moderately severe disease.20 End-stage pulmonary hypertension may require heart-lung transplantation. Traditionally scleroderma patients have been considered poor candidates for transplantation. However, a recent report of 12 patients with scleroderma-associated pulmonary artery hypertension who underwent transplantation suggests similar beneficial outcomes compared to those with other acquired lung diseases.21
Other less common causes of pulmonary hypertension should not be overlooked in scleroderma patients, including recurrent thromboembolic disease. This may be a particular problem in patients with antiphospholipid antibodies.
Hypertensive Renal Crisis
Until recently, hypertensive renal crisis in patients with scleroderma was the major cause of mortality. The advent of angiotensin-converting enzyme (ACE) inhibitors thrust pulmonary disease into the role of leading cause of death in scleroderma. Nonetheless even recent studies of patients with scleroderma renal crisis suggest a continued high mortality rate in this subset of patients.22 Therefore strategies for prevention of scleroderma renal crisis are crucial. Scleroderma renal crisis typically develops in patients with diffuse cutaneous disease and rarely in patients with limited cutaneous disease or CREST.23 At its onset patients experience a marked increase in blood pressure that may be accompanied by abnormalities of urinary sediment (erythrocytes and protein) and the peripheral blood smear (fragmented cells) and thrombocytopenia. Headache, visual disturbance, congestive heart failure, and mental status dysfunction may accompany the hypertension.
The pathogenesis of hypertensive renal crisis is complex and involves a very high renin state. Although combinations of older antihypertensive agents were occasionally successful, the advent of ACE inhibitors has revolutionized the outlook for this problem. Rheumatologists have a low threshold for using these agents in scleroderma patients and typically initiate them at the first diagnosis of hypertension.
In the setting of acute hypertensive renal crisis, larger doses of ACE inhibitors should be used. Although captopril, enalapril, and newer ACE inhibitors have all been used, some prefer captopril because the dose can be adjusted more flexibly. Angiotensin receptor blockers, calcium channel blockers, prostacyclin, and endothelin receptor antagonists have all been suggested as adjunctive therapy for patients refractory to maximum doses of ACE inhibitors.24
Some patients may progress to complete renal failure despite blood pressure control. Continued use of ACE inhibitors and dialysis may be required for months prior to recovery of renal function. Such improvement can continue for up to 2 years.
Progressive renal failure can occur in the absence of significant hypertension in as many as 10% of patients with scleroderma renal crisis. Microangiopathic changes may be seen on peripheral smear. Treatment with ACE inhibitors is indicated for this normotensive subset of patients.
Very ill patients in the ICU may be weak and have elevations of creatine phosphokinase (CPK). Such clinical data prompt speculation about the presence of immune-mediated myositis. The most common presentation of polymyositis is the insidious onset of proximal muscle weakness, at times associated with myalgia. The acute development of de novo polymyositis in the ICU is unlikely. Similarly, acute fulminant disease requiring ICU admission with subsequent diagnosis is uncommon. Nonetheless, patients with undiagnosed polymyositis may be discovered in the ICU following admission for another reason (e.g., aspiration pneumonia). More likely is the presence of weakness (usually generalized) in combination with a spurious or nonimmune cause of CPK elevation. Intramuscular injections and myonecrosis during severe episodes of hypotension are common causes of increased CPK levels in critically ill patients. ICU-acquired myopathy can usually be distinguished from polymyositis by clinical history. Critical illness myopathy is usually characterized by normal or modestly elevated serum CPK levels.25
The skin lesions of dermatomyositis are so highly characteristic as to be diagnostic of dermatomyositis when accompanied by weakness and an elevated CPK value. Nearly all patients with active polymyositis will display an elevated CPK or aldolase level, although occasional patients will have normal muscle enzymes.26 A unilateral electromyogram (EMG) can provide supportive evidence for the presence of myopathy and identify a biopsy site. Fibrillation potentials suggest active inflammation. A bedside EMG can be done in the ICU, although technical artifact may complicate the interpretation. Magnetic resonance imaging (MRI) may also confirm the presence of inflammatory muscle disease, but is generally impractical for ICU patients.
The EMG should be done unilaterally because EMG needle artifact may be confused with muscle inflammation histologically. Because polymyositis/dermatomyositis is a symmetrical disease, the corresponding maximally affected muscle group can be biopsied on the opposite side. Open biopsy can be done at the bedside, preferably by an experienced surgeon to ensure proper handling of muscle tissue. Needle biopsy of muscle using a Polley-Bickel needle is advocated by some and appears suitable for providing confirmation of active muscle inflammation.
Patients with polymyositis/dermatomyositis may develop respiratory failure secondary to muscle weakness involving the diaphragm, intercostals, and accessory muscles. If pharyngeal muscles are involved, acute respiratory failure may be precipitated by aspiration pneumonia. Patients with respiratory failure have a poor prognosis.27 Some patients with dermatomyositis and this type of profound weakness harbor an underlying malignancy. Such patients are notably refractory to treatment.
Steroids are the mainstay of acute management of inflammatory myositis. Prednisone, 1 to 2 mg/kg per day or its approximate intravenous equivalent of methylprednisolone (in single or divided doses) may be given. In the ventilator-dependent patient, a short trial of pulse steroids may be justified—500 to 1000 mg methylprednisolone intravenously every day for 3 days. Improvement in respiratory muscle strength can be judged by a rise in the maximal inspiratory pressure. Intravenous immunoglobulin (IVIg) is another option for the acute management of the severely ill patient refractory to therapy with corticosteroids.28 Second-line agents in polymyositis/dermatomyositis include methotrexate, azathioprine, and cyclophosphamide. Azathioprine is not useful in the acute setting owing to slow onset of action. Methotrexate is most commonly used after corticosteroids. In the ICU setting the intravenous route of administration may be preferred; the dose is 25 to 75 mg intravenously weekly.
Uncontrolled trials with plasmapheresis and combination plasmapheresis and leukocytapheresis have reported benefits and may be considered in refractory patients.29,30 However, a randomized double-blind trial comparing plasmapheresis, leukapheresis, and sham pheresis in 39 patients with polymyositis and dermatomyositis showed comparable improvements in the three treatment groups.31 The role for therapeutic pheresis in patients refractory to conventional therapy seems limited.
Oral low-dose methotrexate given intermittently emerged as the major therapeutic innovation in the treatment of rheumatoid arthritis (RA) during the 1980s. In the era of biological therapies methotrexate continues to be the gold standard of RA therapy and a frequent adjunct to cytokine-directed therapy. Methotrexate therapy is both highly effective and generally well tolerated. A major, albeit uncommon, toxicity is an acute pneumonitis characterized by dyspnea and nonproductive cough.32,33 Fever is a frequent accompaniment.34 Diffuse alveolar and interstitial infiltrates are present at diagnosis or appear within days. Opportunistic infections mimicking this syndrome have only rarely been reported.35 According to one study risk factors for the development of methotrexate-induced lung injury include elderly patients, diabetes, and underlying rheumatoid pleuropulmonary disease.36 Patients suffer profound hypoxemia. They appear extremely ill, and deaths have been reported. The mechanism is unclear but is presumed to be a hypersensitivity reaction to the drug. Some patients have been rechallenged without developing the syndrome while others have relapsed.
Diagnosis depends on the above clinical scenario developing in a patient taking methotrexate at any dose. Duration of treatment prior to symptoms has been variable. Bronchoscopy with brushings and biopsy shows nonspecific inflammation, and bronchoscopy's main justification is to rule out an opportunistic infection. Because these are rare, it is not unreasonable to forego bronchoscopy initially. Open-lung biopsy is usually unnecessary.
Treatment includes O2, withdrawal of drug, and corticosteroids. Some have argued that steroids are not critical to recovery. The usual dose is prednisone 1 mg/kg per day or its equivalent in single or divided doses. Most patients will show signs of recovery within a week. Eventually, recovery is typically near complete.
Cervical Spine Subluxation
Arthritis commonly affects the cervical spine in rheumatoid arthritis, with estimates as high as 80% of patients. Subluxation of vertebrae secondary to ligamentous laxity may occur at single or multiple levels. Anterior atlantoaxial subluxation of C1 on C2 is the most frequent cervical abnormality and is particularly dangerous because of the capacity of the odontoid process (or dens) of C2 to compress the anterior spinal cord with motion. Thus sudden hyperextension of the neck during intubation could result in quadriplegia. In reality such occurrences are rare. The explanation may in part include the fact that progressive resorption of the dens often accompanies the most severely unstable necks. Symptomatic patients can be diagnosed with MRI or a myelogram. However, some dramatic subluxations on MRI are not accompanied by neurologic signs or symptoms. Flexion and extension films of the cervical spine may show dynamic instability and subluxation of C1 on C2. There are few data about the specificity or sensitivity of such films to predict a cervical cord catastrophe. Clearly, caution should be exercised in the intubation of patients with rheumatoid arthritis and neck disease; if time allows, nasotracheal or fiberoptically guided endotracheal intubation is preferred. However, when the risk of delayed intubation is sufficiently great, the procedure should not be delayed for radiographic studies, because the risk of cord catastrophe is quite low. Cervical instability is a problem that attends advanced destructive rheumatoid arthritis. Early aggressive treatment of RA patients with disease-modifying therapy has dramatically reduced the prevalence of this problem.37
Outcomes of Patients with Rheumatologic Diseases in the Intensive Care Unit
Mortality rates for patients with systemic rheumatic diseases admitted to the ICU is high.38 This is perhaps not unexpected when consideration is given to a typical scenario of a chronically ill patient with multiple impaired organs, a disordered immune system, treatment with chronic immunosuppression, and admission to the ICU with infection. Reported ICU mortality rates for patients with rheumatic disease are higher than would be predicted using the Acute Physiology, Age, and Chronic Health Evaluation II or simplified acute physiology score II (SAPS).39,40 Factors associated with poor outcome include higher SAPS II scores, poor health status prior to admission, duration of rheumatic disease, corticosteroids and immunosuppressive drugs, renal failure, coma, and acute respiratory distress syndrome. The overall ICU mortality rate for patients with rheumatic disease ranges from 30% to 60%.38 Mortality rates are higher for patients admitted because of infection compared to those admitted for exacerbation of rheumatic disease.39,40 Since infection may cause two-thirds of ICU admissions among patients with rheumatic disease, aggressive intense therapy of the febrile patient with broad-spectrum antibiotic coverage is appropriate.