In ANCA vasculitis, whatever it is, these antibodies have been shown to be related to the activity of the disease, but at no time are changes in treatment obligatory due to their levels. In this case, with the patient being asymptomatic and with objective evidence of lack of activity, close follow-up should be performed without restarting or modifying treatment.

A 50-year-old man diagnosed with polyangiitis with granulomatosis 10 years earlier and untreated for the past 5 years is asymptomatic at a scheduled check-up. Chest X-ray, blood tests and urine sediment are normal except for positive anti-neutrophil cytoplasmic antibodies (ANCA) at titer 1/320, with anti-proteinase 3 specificity, which had previously been negative. What is the most advisable therapeutic approach?

Initiate treatment with cyclophosphamide.

Initiate treatment with mycophenolate mofetil.

A case of (double) ANCA-negative granulomatosis with polyangiitis (Wegener's).

A 60-year-old man had experienced cough, bloody sputum, and a 38 °C fever for 1.5 months. He visited an outpatient clinic and received antibiotics and nonsteroidal anti-inflammatory drugs. However, because the symptoms continued, he visited our hospital. The past medical history included chronic sinusitis, hypertension, and diabetes mellitus. A chest x-ray film and computed tomography showed multiple pulmonary nodules with cavities. Macrohematuria had developed 3 days before admission, and renal function had deteriorated (creatinine, 2.45 mg/dL) in 2 weeks. He was admitted to our hospital because of rapidly progressive glomerulonephritis (RPGN) and multiple pulmonary nodules. On admission, the clinical diagnosis was suspected to be granulomatosis with polyangiitis (Wegener's) (GPA), although tests for proteinase-3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) were negative. Antibiotics were administered for 5 days. After renal biopsy, methylprednisolone pulse therapy and cyclophosphamide pulse therapy were performed. The pathological diagnosis on the basis of the renal biopsy was glomerular and interstitial hemorrhage, possibly associated with vasculitis. After the treatment, the pulmonary symptoms, multiple pulmonary nodules, and severe inflammatory reactions in the peripheral blood were resolved. However, renal dysfunction progressed to end-stage renal disease 1 month after renal biopsy. Hemodialysis was started, and the steroid therapy was continued. During hemodialysis, a second renal biopsy was performed and led to a diagnosis of pauci-immune focal segmental crescentic glomerulonephritis. Renal function gradually recovered, and hemodialysis was discontinued. This case was (double) ANCA-negative GPA which presented prominent glomerular and interstitial hemorrhage, may be associated with small vessel vasculitis, but without active necrotizing and crescentic glomerular lesions, in the rapidly progressive glomerulonephritis.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

Churg-Strauss syndrome, Eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that affects small- to medium-sized vessels. It is rare and part of the Anti-neutrophil cytoplasm antibody-associated vasculitis (ANCA) group. We present a 37-year-old man, with a previous history of asthma, that was sent to the ED due to 2 weeks of productive cough, occasional dyspnea on exertion, fever (one week), asthenia, and anorexia. Upon physical examination, he was subfebrile and tachycardic. He had leukocytosis (17.00 x10^9/L) and eosinophilia of 20.0 % (3.4 X10^9/L), creatinine level of 1.5 mg/dL, subtle elevation on liver function tests and CRP of 10.82mg/dL. On Chest X-Ray, there was infiltrate on the right pulmonary base. Due to a strong suspicion of EGPA, he was started on 80mg of prednisolone from admission. ANCA MPO was positive, with the remaining auto-immune study negative. He underwent Thorax CT (under corticotherapy) without relevant changes, as well as bronchoalveolar lavage, without macroscopic signs of alveolar hemorrhage. Because of active urinary sediment, nephrotic proteinuria (6.5g/24h), and acute renal failure he underwent a renal biopsy, which revealed pauci-immune crescentic glomerulonephritis, with predominantly acute findings (in the context of ANCA-MPO Vasculitis - EGPA). After the biopsy, he received three 1g methylprednisolone pulses and was started on Cyclophosphamide. He remained asymptomatic and renal function was restored. This case highlights the importance of integrating all findings in one clinical scenario to prevent a more complex disease diagnosis, with a specific treatment, from being missed.

A Case of Granulomatosis with Polyangiitis: Consequences of Delayed Diagnosis in a Life-threatening Malady.

Granulomatosis with polyangiitis (GPA) is one of three described anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Early diagnosis and treatment of GPA is paramount, as it may help prevent irreversible end-organ damage, especially renal and pulmonary failure. A 72-year-old male with a past medical history of lung adenocarcinoma in remission, chronic sinusitis status-post multiple sinus surgeries, and coronary artery disease presented with shortness of breath, dark urine, and asymmetric polyarthralgias. He had an acute kidney injury, leukocytosis, with urinalysis demonstrating pyuria and hematuria, without casts. Chest imaging showed cavitary nodular opacities in addition to interval increase of existing nodules compared to the most recent scan one month prior. His acute kidney injury progressed to renal failure requiring hemodialysis, and he developed an inflammatory polyarthritis. GPA was suspected clinically so he was started on high-dose intravenous corticosteroids, and subsequently plasmapheresis and rituximab. Serology returned with highly positive proteinase-3 antibodies, and cytoplasmic ANCA positivity on immunofluorescence. Renal biopsy demonstrated severely active pauci-immune glomerulonephritis. Several months after discharge, the patient passed away from gram positive bacteremia. This patient's recurrent sinusitis, pulmonary nodules, and subsequent renal failure were highly suggestive of GPA. A biopsy is recommended to confirm the diagnosis of GPA, but treatment should not be delayed if there is a high index of suspicion for the disease. Induction therapy with corticosteroids combined with rituximab or cyclophosphamide has significantly decreased the mortality of patients with GPA. Patients with GPA often have preceding history of nasopharyngeal and upper airway disease, and can present with fluctuating pulmonary infiltrates. Early recognition and treatment of patients with GPA can prevent life-threatening complications and reduce mortality.

Systemic vasculitis in a kidney transplant population.

Systemic vasculitis as original disease might adversely influence the result of kidney transplantation. The clinical course after 32 transplantations to 26 patients with microscopic polyangiitis, Wegener's granulomatosis, Henoch-Schonlein purpura, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, or Goodpasture's disease was evaluated. The median follow-up time was 82 months (range, 4-132 months). Frozen sera from 25 transplantations were analyzed for Goodpasture antibodies, myeloperoxidase antineutrophil cytoplasmic antibodies (ANCA), and proteinase 3 ANCA. Survival of patients and grafts did not differ between patients and matched controls. Recurrent vasculitis occurred with seven grafts (four patients with microscopic polyangiitis or Wegener's granulomatosis, two patients with Henoch-Schonlein purpura, and one patient thrombotic thrombocytopenic purpura). New-onset hematuria was the initial renal symptom in five patients. Treatment with corticosteroids, cyclophosphamide, and/or plasma exchange was most often effective, but two grafts were lost. Proteinase 3 ANCA titers were increased to 12-738 U/ml before seven transplants. The patient with the lowest titer lost his graft due to recurrence, two other patients had reversible recurrence after 1 year and 5 years, two patients lost their grafts due to unknown/unrelated causes, and two patients' grafts remain without recurrence. Myeloperoxidase ANCA were increased to 22-39 U/ml before two transplants, which have been uneventful for 4 years. An awareness of the small but perpetual risk of recurrence facilitates early treatment that may save the transplant. Testing for hematuria and early transplant biopsies, and possibly monitoring of ANCA titers, are essential, but pretransplant ANCA titers have no predictive value in asymptomatic patients. Results of kidney transplantation in patients with vasculitis are as good as in other patients.

[Acute onset Wegener's granulomatosis presenting as otitis media; a case report].

We report the case of a 57-year-old woman with Wegener's granulomatosis who presented with otitis media. The patient presented with a 2-month history of bilateral hearing loss and dizziness. Antibiotic treatment was not effective, and the patient was confirmed to have bilateral sensorineural hearing loss. Serum was positive for cytoplasmic anti-neutrophil cytoplasmic antibody [C (PR3)-ANCA] but negative for P(MPO)-ANCA (perinuclear ANCA). While the test results were pending, the patients' general condition worsened ; in particular, signs of active inflammation, cardiorespiratory failure and scleritis developed suddenly. Emergency chest computed tomography revealed evidence of lung involvement and hydrothorax; thus, the patient was diagnosed to have the generalized form of Wegener's granulomatosis. The patient was started on pulse methylprednisolone therapy at 1000mg/day for 3 days, which resulted in marked clinical improvement, and then, the drug therapy was switched to prednisolone 60mg/day and cyclophosphamide 50mg/day and gradually tapered. Early diagnosis of Wegener's granulomatosis is often difficult because of atypical manifestations of the disease; particular attention must be paid to acute onset of the disease, such as in our case. ANCA is a very useful marker for early diagnosis, but about one week is needed to obtain the test results. We believe that early steroid and cyclophosphamide therapy is an effective therapeutic option for patients with signs of severe inflammation and generalized involvement.

Double-positive Goodpasture's syndrome with concomitant active pulmonary tuberculosis.

Anti-glomerular basement membrane (anti-GBM) disease usually presents as rapidly progressive glomerulonephritis, and, when accompanied with pulmonary hemorrhage, it is called Goodpasture's syndrome. Anti-neutrophilic cytoplasmic antibodies (ANCA) may co-exist with anti-GBM antibodies. In most of these "double positive" cases, ANCA is specific for myeloperoxidase (p-ANCA). We report a rare case of a critically ill patient c-ANCA-associated double-positive Goodpasture's syndrome with concomitant tuberculosis that was successfully treated with immunosuppression, plasmapheresis and anti-tuberculous therapy (ATT). A 32-year-old gentleman with a 15 pack-year smoking history presented with massive hemoptysis, respiratory failure and oliguria. Laboratory investigation revealed anemia, elevated creatinine and active urinary sediment. Chest X-ray revealed bilateral pulmonary infiltrates. Broad-spectrum antibiotics and intravenous corticosteroids were started. Bronchoscopy showed alveolar hemorrhage and smears from bronchial lavage from both lungs were positive for acid fast bacillus (AFB). Vasculitis work-up revealed high titers of c-ANCA and anti-GBM antibodies. Kidney biopsy revealed crescents in >50% glomeruli on light microscopy. Immunofluorescence showed linear deposition of IgG and C3. The patient received pulse methylprednisone for three days followed by oral prednisone and ATT. In addition, he also underwent nine sessions of plasmapheresis. Oral Cyclophosphamide was added on Day 10. The patient showed remarkable recovery as his lung fields cleared and his kidney function got stabilized. Cyclophosphamide was continued for three months and then switched to azathioprine. At six months, the creatinine is 1.2 mg/dL, with minimal proteinuria and a normal chest X-ray. To the best of our knowledge, this is the only reported case of double-positive Goodpasture's syndrome (c-ANCA and anti GBM) with active tuberculosis treated successfully.

A clinical case of recurrent episcleritis as the initial manifestation of granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a type of small-sized blood vessel vasculitis that predominantly affects the upper airways, lungs and kidneys and associates with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Nevertheless, any organ of the body can be affected by GPA, including the eye. Occasionally, ocular involvement can be the initial manifestation, thus representing an essential clue for the physician in the early diagnosis of the disease. We present the case of a 53-year-old woman in whom recurrent episcleritis was the first sign of a multisystem disease. All further investigations led to the final diagnosis of GPA. The remission induction therapy chosen by the rheumatologist consisted of intravenous cyclophosphamide (CP) and methylprednisolone pulse-therapy, followed by oral glucocorticoids (GC). Based on the favorable clinical and paraclinical evolution, induction therapy was replaced by remission maintenance therapy. Azathioprine (AZA) was initiated and oral GC were continued, with dose tapering. Complete remission of episcleritis was observed. <bAbbreviations:</b GPA = granulomatosis with polyangiitis, EGPA = eosinophilic granulomatosis with polyangiitis, MPA = Microscopic polyangiitis, ANCA = Anti-neutrophil cytoplasmic antibodies, c-ANCA = ANCA to proteinase-3, p-ANCA = ANCA to myeloperoxidase, ELISAs = antigen-specific enzyme-linked immunosorbent assays, ENT = ear, nose, throat, CP = cyclophosphamide, NSAIDs = nonsteroidal anti-inflammatory drugs, AZA = azathioprine, GC = glucocorticoids.

Granulomatosis with polyangiitis

Diagnosis Granulomatosis with polyangiitis is usually suspected only when a person has had unexplained symptoms for a long period of time. Determination of anti-neutrophil cytoplasmic antibodies (ANCAs) can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. More than 90% of people who have GPA test positive for ANCA. Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with GPA. Involvement of the ears, nose, and throat is more common in granulomatosis with polyangiitis than in the similar condition microscopic polyangiitis.

Granulomatosis with polyangiitis

Trimethoprim/sulfamethoxazole has been proposed to help prevent relapse though a 2015 Cochrane review did not confirm fewer relapses with trimethoprim/sulfamethoxazole treatment. Prognosis Before modern treatments, the 2-year survival was under 10% and average survival five months. Death usually resulted from uremia or respiratory failure. The revised Five-factor score is associated with 5-year mortality from GPA and is based on the following criteria: age greater than 65 years, cardiac symptoms, gastrointestinal involvement, chronic kidney disease, and the absence of ears, nose, and throat symptoms. With corticosteroids and cyclophosphamide, 5-year survival is over 80%. Long-term complications are common (86%), mainly chronic kidney failure, hearing loss, and deafness. The risk of relapse is increased in people with GPA who test positive for anti-PR3 ANCA antibodies and is higher than the relapse risk for microscopic polyangiitis.

Granulomatosis with polyangiitis: An atypical initial presentation.

Granulomatosis with polyangiitis (GPA) is a necrotizing vasculitis of small and medium vessels with involvement of the upper and lower respiratory tract and necrotizing pauci-immune glomerulonephritis [1]. This vasculitis has a higher incidence in men in the sixth decade of life and more than 80% of patients have positive anti-neutrophil cytoplasm (ANCA) antibodies [1,2]. We present the case of a 23-year-old man with two weeks of evolution with polyarthralgia, asthenia, and cough with hemoptoic sputum. He did a chest radiography that showed diffuse bilateral alveolar infiltrates, on the second stage. The patient presented a rapid clinical worsening, with moderate hemoptysis and severe respiratory failure requiring invasive mechanical ventilation. The autoimmune study revealed positivity for ANCA PR3 in titer >200, having started pulses of methylprednisolone, plasmapheresis and later cyclophosphamide, with clinical improvement. His high-resolution chest computed tomography (CT) showed areas of diffuse ground glass densification suggesting capillaritis/alveolar hemorrhage and two subpleural nodular areas suggestive of granulomatous vasculitis. CT of the nasal sinuses showing findings compatible with acute inflammatory changes, with histology of the nasal mucosa inconclusive. Thus, this case shows an exuberant and potentially fatal form of diffuse alveolar hemorrhage that culminated in the initial diagnosis of granulomatous vasculitis in a young adult.

Rapidly progressive glomerulonephritis

Type III Also known as pauci-immune RPGN, type III RPGN accounts for 55% of RPGN and features neither immune complex deposition nor anti-GBM antibodies. Instead, the glomeruli are damaged in an undefined manner, perhaps through the activation of neutrophils in response to ANCA. Type III RPGN may be isolated to the glomerulus (primary, or idiopathic) or associated with a systemic disease (secondary). In most cases of the latter, the systemic disease is an ANCA-associated vasculitis such as granulomatosis with polyangiitis, microscopic polyangiitis or eosinophilic granulomatosis with polyangiitis. Treatment Therapy consists of a combination of rituximab, corticosteroids, and cyclophosphamide, with a substitution of azathioprine for cyclophosphamide after a ninety-day initial period being another option. When remission is achieved, immunosuppressants are still used, usually corticosteroids with azathioprine or rituximab infusions.

Relationship between disease activity and anti-neutrophil cytoplasmic antibody concentration in long-term management of systemic vasculitis.

Autoantibodies directed against neutrophil cytoplasmic antigens (ANCA) are valuable in the diagnosis of primary systemic vasculitis, and immunofluorescence studies suggest that changes in ANCA concentration reflect changes in disease activity. We used enzyme-linked immunosorbent assays to examine retrospectively the relationship between ANCA concentration and disease activity in 56 patients with systemic vasculitis. We included patients with Wegener's granulomatosis, microscopic polyangiitis, idiopathic rapidly progressive glomerulonephritis, and Churg-Strauss syndrome, and examined separately the initial treatment period (mean length of follow-up, 26 months) and long-term management (mean length of follow-up, 59 months). Levels of ANCA decreased during induction therapy with prednisolone and cyclophosphamide, with or without plasma exchange. During follow-up, 27 relapses were documented in 20 patients (10 with Wegener's granulomatosis, nine with microscopic polyangiitis, and one with Churg-Strauss syndrome), occurring between 4 and 183 months (mean, 62 months) after initial presentation. Patients in whom ANCA were detectable 1 year or more after treatment were at particular risk of clinical relapse. Proteinase 3-directed ANCA appeared to be associated with a higher rate of relapse (44% of patients relapsed) than myeloperoxidase-directed ANCA (13% of patients relapsed). Twenty-four of the 27 relapses occurred in the presence of detectable ANCA; in 21 of these, ANCA concentration was high or rising. The temporal relationship between changes in ANCA concentration and clinical relapse varied considerably between patients; in seven patients, ANCA remained at high levels for many months (range, 14 to 67 months) before eventual relapse. One patient showed high concentrations of ANCA over a period of 11 years without relapse. In five patients, increases in the ANCA level were not temporally associated with relapse (although four of these patients relapsed on other occasions.) We conclude that monitoring ANCA by enzyme-linked immunosorbent assays is of value in the long-term management of patients with Wegener's granulomatosis, microscopic polyangiitis, idiopathic rapidly progressive glomerulonephritis, and Churg-Strauss syndrome. Increases in ANCA and persistently high levels point to the risk of relapse and indicate the need for frequent clinical review and continuing maintenance immunosuppression. However, our results suggest that ANCA assays should always be used in conjunction with other indices of disease activity and should not be the sole basis for changing therapy.

Pulmonary renal syndrome in a child with coexistence of anti-neutrophil cytoplasmic antibodies and anti-glomerular basement membrane disease: case report and literature review.

Pulmonary renal syndrome (PRS), denoting the presence of diffuse alveolar hemorrhage and glomerulonephritis as manifestations of systemic autoimmune disease, is very rare in childhood. The coexistence of circulating anti-neutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) disease in children affected by this syndrome is exceptional, with unfavorable outcome in five out of seven patients reported to date. We describe a child with PRS associated with both circulating anti-myeloperoxidase (anti-MPO) ANCA and anti-GBM disease on renal biopsy who was successfully treated with immunosuppressive therapy. A 10-year old girl presented with fever, fatigue, malaise, and pallor followed by hemoptysis and severe anemia. Diffuse alveolar hemorrhage was revealed on fiberoptic bronchoscopy. Renal findings consisted of microscopic hematuria, moderate proteinuria, and anti-GBM disease on renal biopsy. ANCA with anti-MPO specificity were present whereas anti-GBM antibodies were on borderline for positivity. Methyl-prednisolone pulses followed by prednisone led to cessation of hemoptysis, marked improvement of lung fuction, and normal finding on chest x-ray within 10 days. An immunosuppressive regimen was then given consisting of prednisone daily for 4 weeks with subsequent taper on alternate day, i.v. cyclophosphamide pulses monthly for 6 doses, followed by mycophenolate mofetil that resulted in normal lung function tests, hemoglobin concentration, and anti-MPO level within four subsequent weeks. During 10-months of follow-up she remained well, her blood pressure and renal function tests were normal, and proteinuria and hematuria gradually resolved. We report a child with an exceptionally rare coexistence of circulating ANCA and anti-GBM disease manifesting as PRS in whom renal disease was not the prominent part of clinical presentation, contrary to other reported pediatric patients. A review of literature on disease with double positive antibodies is also presented. Evaluation of a patient with PRS should include testing for presence of different antibodies. An early diagnosis and rapid institution of aggressive immunosuppressive therapy can induce remission and preserve renal function. Renal prognosis depends on the extent of kidney injury at diagnosis and appropriate treatment.

[An old man presenting with fluctuating bilateral multiple cranial nerve palsies and positive test for perinuclear antineutrophil cytoplasmic antibody].

A 70-year-old man admitted to a local hospital because of facial muscle weakness, tinnitus and facial pain in left side, was then given corticosteroid with a tentative diagnosis of Bell's palsy and his symptoms gradually improved. Since these symptoms recurred six months later, he was referred to our neurological service. As his brain CT revealed diffuse thickening and enhancement of the dura mater, he was thought to have hypertrophic pachymeningitis (HP). Intravenous antibiotics were started for aspiration pneumonia and his neurological symptoms gradually improved. HP caused by bacterial infection was thus likely and antibiotics, rifampicin and metronidazole, were administered orally as an outpatient. However, one month later, these symptoms were worsened with headache and double vision. He was then rehospitalized. MR imagings of the head with gadolinium disclosed diffuse meningeal thickening and enhancement, especially of the left-sided cerebellar tentorium. Erythrocyte sedimentation rate and C-reactive protein were moderately elevated. Serum angiotensin converting enzyme was within normal range. The test for cytoplasmic antineutrohil cytoplasmic antibody (ANCA) in the serum was negative, however, that for perinuclear ANCA was positive at a titer of 99 EU. Lumbar puncture showed normal findings and negative culture results for bacteria, fungi or mycobacteria. Dural biopsy specimens showed non-specific granulomatous inflammation of the dura with epithelioid histiocytes and Langerhans type multinuclear giant cells with caseous necrosis, however, with no presence of fungi or tubercle bacilli. After the oral administration of cyclophosphamide (100 mg, daily) and prednisolone (40 mg, daily), his neurological symptoms and laboratory findings have been gradually improved and he is well one year after discharge. This case together with previous reports suggests that ANCA positive HP without evidence of other organ involvements may belong to the limited form Wegener's granulomatosis. In the literatures of idiopathic HP, the treatment effect with corticosteroid alone is initially favorable, but transient. On the other hand, using the combined therapy of cyclophosphamide and prednisolone, the remission has been achieved in more than 90% of patients with WG. These data suggest that P-ANCA positive HP should be treated with a combination of corticosteroid and cyclophosphamide.

Granulomatosis with Polyangiitis (Wegener Granulomatosis) with Unusual Presentation.

We came across a 32 years old male admitted in our hospital with prolonged low-grade fever, haemoptysis, leg swelling, weight loss, purpuric rashes and malaena. He received anti-TB treatment at another hospital without any improvement. He was pale with bullous and purpuric lesions over legs and feet. He also had features of consolidation over both lung fields. His CRP was 312mg/L, Urine R/M/E showed 40-50 RBC/HPF, Chest X-ray showed features of bilateral consolidation, c-ANCA-10U/L (positive); Tracheal aspirate for AFB was found to be negative. We diagnosed the case as Granulomatosis with Polyangitis (WG) and started treatment with steroid and cyclophosphamide. But the patient could not be saved probably due to delay in starting management.

Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis.

To assess the value of serial determinations of antineutrophil cytoplasmic autoantibodies (ANCA) for monitoring disease activity in patients with systemic vasculitis. Forty-three patients with histologically proven vasculitis (21 with Wegener's granulomatosis, 17 with microscopic polyangiitis, and 5 with renal-limited vasculitis) were studied for a median follow-up of 22 months. Disease activity was prospectively assessed and quantified by the Birmingham Vasculitis Activity Score. A total of 347 sera were analyzed for ANCA determination. Relapses occurred in 23 (54%) of 43 patients. Diagnostic category (Wegener's granulomatosis vs micropolyangiitis and renal-limited vasculitis), severity of initial symptoms (mean vasculitis activity score, mean number of organs involved), and ANCA pattern [cytoplasmic-ANCA (c-ANCA) vs perinuclear-ANCA (p-ANCA)] did not significantly differ between relapsers and nonrelapsers. Lung involvement was more frequent at onset among relapsers [16 of 23 (70%) vs 6 of 20 (30%); P = 0.02]. Relapses were slightly, but not significantly, more frequent in patients with Wegener's granulomatosis or a c-ANCA pattern. The percentage of relapsers was greater in patients with persistently positive ANCA than in patients with negative or decreasing ANCA titers (86% vs 20%, P = 0.0001). However, the predictive value of an increase in ANCA titers for the occurrence of a subsequent relapse was only 28% (4 of 14) for c-ANCA, 12% (2 of 17) for anti-proteinase 3-ANCA, and 43% (6 of 14) for anti-myeloperoxidase-ANCA. An increase in ANCA occurred before or during relapse in 33% (10 of 30) of cases for c-ANCA/anti-proteinase 3 antibodies, and 73% (11 of 15) of cases for anti-myeloperoxidase antibodies. The persistence of ANCA positivity is strongly associated with relapses. However, an increase in ANCA titers has a poor value for the early prediction of a subsequent relapse and should not be used as a sole parameter for therapeutic intervention. In addition, our results suggest that serial anti-myeloperoxidase determination may be useful as a prognostic marker in patients who are p-ANCA positive.

C-ANCA

c-ANCAs, or PR3-ANCA, or antineutrophil cytoplasmic antibodies, are a type of autoantibody, an antibody produced by the body that acts against one of its own proteins. These antibodies show a diffusely granular, cytoplasmic staining pattern under microscopy. This pattern results from binding of ANCAs to antigen targets throughout the neutrophil cytoplasm, the most common protein target being proteinase 3 (PR3). For example, PR3 is the most common antigen target of ANCA in patients with granulomatosis with polyangiitis. In active granulomatosis with polyangiitis, c-ANCA is found over 90% of the time. Other antigens may also occasionally result in a c-ANCA pattern. See also P-ANCA Anti-Neutrophil Cytoplasmic Antibody (ANCA) References Autoantibodies

[Granulomatosis with polyangiitis (Wegener). Description of 15 cases].

Granulomatosis with polyangiitis (GP) is a necrotizing vasculitis of unknown etiology that involves small and medium caliber vessels. It is associated with anti neutrophil cytoplasm antibodies (ANCA). It most often affects the respiratory tract and the kidneys and its most important pathologic feature is the presence of necrotizing granulomas. To detail the features of 15 patients with GP diagnosed in a university referral center. Retrospective study: between 1984 and 2009, 15 patients with GP were diagnosed in our center. Epidemiological, clinical, laboratory test as well as pathologic studies and treatment were retrospectively analyzed. Biopsy diagnosis of GP was considered as an inclusion criterion. Fifteen patients were diagnosed: 12 men and 3 women. Mean age at diagnosis: 52.2 years (14-78). 12 patients had a history of smoking. A biopsy was diagnostic in all patients. ANCA were positive in 11 cases, 6 had a cytoplasmic c-ANCA pattern. All patients had pulmonary involvement and seven (40%) had renal involvement. All patients received intravenous glucocorticoids and cyclophosphamide as induction therapy. During the disease progression 5 patients died. The clinical features of this series do not differ from those described by other authors. However, a history of smoking is more common than expected. Frequently used drugs were glucocorticoids and cyclophosphamide (oral and pulse therapy). The course was usually unfavorable, with outbreaks or complications due to immunosuppression, except for those with limited forms. Immunosuppressive therapy should be maintained indefinitely in most cases.

InternalMed_Harrison

Patients with any of these three diseases can have any combination of the above serum antibodies, but anti-PR3 antibodies are more common in granulomatosis with polyangiitis and anti-MPO antibodies are more common in microscopic polyangiitis or Churg-Strauss. Although each of these diseases has some unique clinical features, most features do not predict relapse or progression, and as a group, they are generally treated in the same way. Since mortality is high without treatment, virtually all patients receive urgent treatment. Induction therapy usually includes some combination of plasmapheresis, methylprednisolone, and cyclophosphamide. Monthly “pulse” IV cyclophosphamide to induce remission of ANCA-associated vasculitis is as effective as daily oral cyclophosphamide but may be associated with increased relapses. Steroids are tapered soon after acute inflammation subsides, and patients are maintained on cyclophosphamide or azathioprine for up to a year to minimize the risk of relapse.

Negative anti-neutrophil cytoplasm antibody at switch to maintenance therapy is associated with a reduced risk of relapse.

Relapse of disease is frequent in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). It is unclear whether persistent ANCA when starting maintenance therapy increases the risk of relapse. We examined the association between ANCA status and relapse in two randomised controlled trials. ANCA-positive patients in two trials, CYCLOPS and IMPROVE, were switched from cyclophosphamide to maintenance therapy after achieving clinical remission. We classified patients as being either ANCA-positive or ANCA-negative at the time they started maintenance therapy. We compared the risk of relapse in ANCA-positive and ANCA-negative patients. Of 252 patients included, 102 (40%) experienced at least one relapse during the follow-up period. At the time of the switch from induction to maintenance therapy, 111 were ANCA-positive, of whom 55 (50%) relapsed, compared to 141 patients who were ANCA-negative, of whom 47 (33%) relapsed. In multivariable time-to-event analysis, a reduced risk of relapse was associated with having become ANCA-negative at the time of switching to maintenance therapy (hazard ratio 0.63, 95% confidence interval 0.42-0.95; p = 0.026). In addition, initial proteinase 3 (PR3)-ANCA, younger age, lower serum creatinine, pulsed cyclophosphamide for remission induction, and mycophenolate mofetil for remission maintenance were all associated with an increased risk of relapse. Becoming ANCA-negative before the switch to maintenance is associated with a reduced risk of relapse. CYCLOPS: ClinicalTrials.gov, NCT00430105 . Registered retrospectively on 31 January 2007. ClinicalTrials.gov, NCT00307645 . Registered retrospectively on 27 March 2006.

[Case of microscopic polyangiitis presenting initially as prostatic vasculitis].

A 79-year-old man was admitted to our hospital to evaluate prostatic vasculitis that was diagnosed on a prostatic biopsy performed due to an elevated prostate-specific antigen (PSA)level. He complained of general malaise and had hematuria, proteinuria, and interstitial pneumonitis in the lower lung field on admission. A renal biopsy showed necrotizing crescentic glomerulonephritis. He was diagnosed as having microscopic polyangiitis (MPA) based on the presence of small-vessel vasculitis and positivity for myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) (465 EU). He was effectively managed with methylprednisolone pulse therapy (500 mg/day x 3 days) followed by progressive dosage tapering. In the present case, the identification of prostatic vasculitis led to the early detection of MPA, which resulted in an excellent clinical course. Prostatic involvement has been also reported in patients with Wegener's granulomatosis or Churg-Strauss syndrome. Thus, physicians should be aware of the potential for the involvement of various organs, including the prostate, in patients with ANCA-associated vasculitis.

Diagnostics and therapy of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides.

Granulumatosis with polyangiitis (wegener's)/GPA microscopic polyangiitis (MPA) and Churg Strauss syndrome (CSS) are primary systemic vasculitides which predominantly affect small vessels, showing a high association with a positive C/PR3-ANCA in GPA and P/MPO-ANCA in MPA, so called ANCA-associated vasculitides (AAV). The diagnostic work-up relies on an interdisciplinary approach including imaging techniques and laboratory tests in order to assess disease stage and extent. The golden standard remains the histological proof of a necrotizing, pauci-immune small vessel vasculitis, in GPA additionally non-caseating granuloma is found mainly in the respiratory tract. Treatment is adapted to disease stage and extent and relies on a combination of a cytotoxic plus a tapering regimen of glucocorticosteroids. Induction of remission in "early systemic" disease without organ- and life-threatening organ manifestations and a near normal kidney function can be achieved with methotrexate. In the generalized phase with significant renal dysfunction cyclophosphamide is the mainstay of therapy, in rapidly progressive glomerulonephritis with an imminent dialysis indication plasmapheresis is performed additionally. When remission is achieved, usually after 3-6 months of induction treatment, cyclophosphamide is switched to azathioprine as maintenance of remission drug. Alternative therapies are methotrexate provided the kidney function is normal or Leflunomide in the long-term follow-up the relapse rate in ANCA-associated vasculitis is approximately 50% in 5 years, irrespective of the drug used for maintenance treatment. The relapse rate is significantly higher in GPA than in MPA and CSS.

Clinical course and symptomatic prediagnostic period of patients with Wegener's granulomatosis and microscopic polyangiitis.

The clinical course of 15 patients with Wegener's granulomatosis (WG) and eight patients with microscopic polyangiitis (MPA) from one nephrological clinical center is presented for the period from 1984 to 1993, when testing for antineutrophil cytoplasmic antibodies (ANCA) was gradually introduced into routine clinical practice. We found a high degree of prolonged time periods with symptoms attributable to WG or MPA until the specific diagnosis was made. Nine patients with WG and one patient with MPA had symptomatic prediagnostic periods of more than three years, which extended in one case up to twenty years. In these prediagnostic periods, often even severe flares of vasculitic activity resulted in spontaneous remission without immunosuppressive therapy. One patient on chronic dialysis for four months because of rapidly progressive glomerulonephritis, experienced sufficient spontaneous regain of residual renal function to stay off dialysis for 6 years. Despite a high amount of spontaneous recovery, recurrent flares of disease eventually led to death in those cases without sufficient immunosuppressive therapy. Contrary to long courses of disease, one patient with WG had a fulminate exacerbation of disease with lethal hemoptysis after a prediagnostic period of only three months. Renal disease, respiratory and other symptoms did not occur sequentially, but each could precede the other. We conclude in agreement with published former experience, that WG and MPA show a highly variable spontaneous disease course, that requires extended observational periods for evaluating maintenance therapies.

Are antineutrophil cytoplasmic antibodies a marker predictive of relapse in Wegener's granulomatosis? A prospective study.

To investigate the predictive value of testing for antineutrophil cytoplasmic antibodies (ANCA) in 55 patients with systemic Wegener's granulomatosis (WG) included in a randomized, prospective trial comparing corticosteroids and oral or pulse cyclophosphamide. All 55 patients received corticosteroids. A cyclophosphamide pulse of 0.7 g/m2 was given at the time of diagnosis. After the first pulse, the patients were assigned at random to receive either pulse or oral cyclophosphamide (2 mg/kg/day), independently of ANCA results. ANCA were sought using an immunofluorescence assay and an attempt was made to correlate them with relapse of WG. ANCA were monitored throughout the study. At the time of diagnosis, ANCA were detected in 48 (87%) patients, with a cytoplasmic labelling pattern in 44 and a perinuclear pattern in four. ANCA follow-up was available for 50 patients. ANCA disappeared in 34 patients and persisted in nine. For 79% of the patients, the clinical course improved with the disappearance of ANCA and deteriorated with their persistence or increased titre. Among the patients who were initially ANCA-positive, 23 relapses occurred. Relapses were more frequent when ANCA remained positive or reappeared [13/19 ANCA-positive patients vs 3/29 ANCA-negative patients (P<0.01)]. Nine relapses (39%) occurred in patients with persistent ANCA, and ANCA reappearance preceded relapse in eight (35%). The mean time between inclusion and relapse did not differ between the patients who became ANCA-negative and those who were persistently ANCA-positive (14.6+/-13.2 vs 14.4+/-8.2 months). The mean time to ANCA disappearance was similar for the patients who relapsed and those who did not. Corticosteroids and pulse or oral cyclophosphamide did not significantly modify the time to ANCA disappearance. Throughout the study, seven patients were ANCA-negative. Although ANCA positivity was associated with relapse, discordance between cytoplasmic ANCA and disease activity was not unusual. In the absence of clinical manifestations, ANCA titres alone can serve as a warning signal but not indicate whether to adjust or initiate treatment.

Treatment of acute c-ANCA-positive vasculitis with mycophenolate mofetil.

Acute cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA)-positive vasculitis is usually treated with cyclophosphamide and corticosteroids. The incidence of cyclophosphamide-induced lung injury, a potentially life-threatening event, is about 1%. We report on a patient with a history of cyclophosphamide-induced lung injury 2 months after initial treatment of systemic c-ANCA-positive vasculitis. Six months later, the patient presented with acute renal failure caused by an acute relapse of vasculitis. Mycophenolate mofetil (MMF) is a potent immunosuppressive drug that recently has been shown to be effective in the maintenance therapy of c-ANCA-positive systemic vasculitis. With the patient's informed consent, we started treatment with MMF in combination with corticosteroids. Subsequently, anti-proteinase-3-titer (anti-Pr3-titer) returned to normal and renal function improved. In conclusion, MMF in combination with corticosteroids may be useful in the treatment of acute c-ANCA-positive vasculitis.

Immunosuppressive therapy and clinical evolution in forty-nine patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis.

Immunosuppressive therapy and clinical evolution were studied in 49 patients (29 females) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The mean age of patients at presentation was 55 years, and the mean (+/-SD) follow-up was 43 months (+/-33) (range, 3-140). Among the 49 patients, 10 had biopsy-proven Wegener's granulomatosis, 33 microscopic polyangiitis, 2 Churg-Strauss syndrome, and 4 idiopathic crescentic glomerulonephritis. IgG ANCA autoantibodies were detected in all patients. Induction therapy included pulses and oral administration of methylprednisolone (MP) with oral administration of cyclophosphamide (CP) and plasma exchange in patients with alveolar hemorrhage and serum creatinine (SCr) levels >/= 6 mg/dL. CP was converted to azathioprine (AZA) or mycophenolate mofetil (MMF) after 3-6 months of therapy. Low doses of MP with or without AZA or MMF were administered until the end of follow-up. Therapy institution resulted in remission of disease in all patients. The mean SCr levels decreased from 4.9 mg/dL (+/-2.5) at the onset of the disease to 2.8 mg/dL (+/-1.7) (P > 0.0001), and 3.2 mg/dL (+/-2.3) (P > 0.0001) after 3 and 6 months, respectively. At the end of follow-up, 17 (35%) patients progressed to end-stage renal disease after 34 months (+/-29) (range, 3-98), and 30 (61%) patients maintained sufficient renal function. Two patient deaths were attributed to immunosuppression. Patients with high SCr levels at diagnosis and severe interstitial fibrosis found in renal biopsy had poor renal outcome (P > 0.01 and P > 0.02, respectively). Induction therapy with MP and CP seems to be the regimen of choice in patients with ANCA-associated glomerulonephritis. Early diagnosis and therapy institution as well as long-term treatment lead to acceptable renal survival.

Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.

In this study, the rate of remission, relapse, and treatment resistance in 107 patients with microscopic polyangiitis and necrotizing and crescentic glomerulonephritis associated with antineutrophil cytoplasmic autoantibodies were assessed. Patients with Wegener's granulomatosis were excluded. Prospective criteria were identified to assess remission, relapse, and resistant disease. Ninety-seven of the 107 patients received treatment with corticosteroids (N = 25) or with cyclophosphamide and corticosteroids (N = 72). Of these patients, 75 (77.3%) went into remission (complete remission, N = 61; remission on therapy, N = 14). Of the 75 responders, 32 patients (43%) remained in long-term remission, for a mean follow-up of 44 +/- 29 months; 15 patients (20%) progressed to ESRD without signs of relapse, for a mean of 21.4 +/- 22.8 months after the end of treatment; 6 patients died. Twenty-two of the 75 patients who initially responded to treatment (29%) suffered a relapse that occurred within 18 months of the end of therapy and usually affected the same organ systems as on initial presentation. There was a significant difference in the remission rate between the corticosteroid-treated patients and the cyclophosphamide-treated patients (56% versus 84.7%, P = 0.003), and the cyclophosphamide-treated patients had three times less risk of experiencing a relapse than did corticosteroid-treated patients (0.31, 95% Cl = (0.12, 0.84)). Seventy-seven percent (17 of 22 patients) of treatment resistance occurred in patients who presented with fulminant disease or advanced and severe renal disease. It was concluded that most patients with microscopic polyangiitis or necrotizing and crescentic glomerulonephritis achieve remission with therapy. Relapses occur in 29% of patients and generally respond to retreatment. Initial treatment with cyclophosphamide and corticosteroids rather than corticosteroids alone results in a lower frequency of relapse. Even patients who require dialysis at presentation may benefit from treatment, however, patients who are not treated until the disease process is life-threatening may die before induction therapy is complete, indicating the continued need for early diagnosis and therapy.

Does a gating policy for ANCA overlook patients with ANCA associated vasculitis? An audit of 263 patients.

Antineutrophil cytoplasm antibodies (ANCA) are used as diagnostic markers for small-vessel vasculitis of the Wegener Granulomatosis-microscopic polyangiitis (WG-MPA) spectrum, but if testing is applied indiscriminately, its value is diminished. The authors measured the effect of a targeted ANCA testing policy introduced in our institution in an attempt to improve the diagnostic value of testing in patients with suspected vasculitis. The authors measured the rate of ANCA requests at a single regional centre in the year prior to and following the introduction of clinical guidelines to ensure appropriate test usage. The authors also audited clinical outcomes in patients in whom ANCA testing was declined. Following implementation of the antineutrophil cytoplasm antibodies (ANCA) gating policy, the number of monthly ANCA tests carried out fell from 287+/-30 to 143+/-18 (p<0.0001) and was associated with an increased rate of positivity, from 18.5% (95% CI 17.0 to 20.1%) to 30.3% (27.5 to 33.1%; p<0.0001). The authors undertook a careful review of the case records from 263 patients in whom testing was declined according to the gating policy over an 8-month period. After 6 months' follow-up, no diagnoses of small-vessel vasculitis of the WG-MPA spectrum were reached. The rational use of ANCA testing to aid in the diagnosis of vasculitis should include a clinical gating policy to improve diagnostic performance. Adherence to a gating policy for ANCA testing coupled with close liaison between clinician and laboratory does not result in either a missed or delayed diagnosis of small-vessel vasculitis belonging to the WG-MPA spectrum.

[ANCA(antineutrophil cytoplasmic antibodies)-associated vasculitis in a man with extreme fatigue, fever and progressive renal dysfunction].

A 55-year-old man, with no previous history, presented with extreme fatigue and fever and was admitted to hospital. He had progressive renal dysfunction and his serum anti-neutrophil cytoplasmic antibodies (ANCA) were markedly elevated. Renal histology was consistent with ANCA-associated vasculitis. The patient was successfully treated with cyclophosphamide and prednisolone. The classification and management of the ANCA-associated vasculitides are described. The classification was guided by the clinical presentation, serology and results of tissue biopsies. The ANCA inflammation had affected the middle sized and small vessels of especially the upper and lower airways, and the kidneys. The antibodies were directed at proteinase-3 (PR3) or myeloperoxidase (MPO). PR3-ANCA is predominantly found in Wegener's granulomatosis, while MPO-ANCA is related to microscopic polyangiitis. Tissue studies showed granulomatous inflammation of the airways which is typical of Wegener's disease. This type of inflammation is absent in microscopic polyangiitis. The initial treatment schedule consists of prednisone 1 mg/kg daily and oral cyclophosphamide 2 mg/kg daily. In the remission phase, the cyclophosphamide is replaced by azathioprine. It is not yet known how long maintenance treatment should be continued and which parameters have prognostic value.

[Use of rituximab in the induction of remission of severe, resistant and recurrent form of polyangiitis associated with c-ANCA antibodies - case report].

Indications for rituximab (RTX) have recently widened. We present a case of 25-years old patient with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis of high disease activity. The patient in severe condition, massive changes of nasal sinuses, with destruction of the orbit bones, with inflammatory infiltrations of the optical nerves and end stage renal disease was admitted to Nephrology Clinic to begin renal replacement therapy (RRT). Chest HRCT reveled changes of "frosted glass", enlarged mediastinal lymphatic nodes and fluid in pleural cavities. C-ANCA antibodies was 23 IU/ml (norm: <2IU/ml). Due to the lack of therapeutic possibilities (exceeded cumulative dose of cyclophosfamide, recurrence of the disease during treatment with mycophenolate mofetil) rituximab was introduced. After proving high expression of CD 20 antigen on the surface of B lymphocytes, two doses of rituximab were administrated (1,0g every two weeks). 8 weeks after the second dose remission of lungs disorders was observed, c- ANCA level decreased to 3,7IU/ml and the granulomatous mass around the optical nerve was stable. 12 months later another supporting dose of rituximab was administrated. Now, 18 months after relapse of the disease patient is in good condition waiting for kidney transplantation. Rituximab is save, well tolerated and effective. Particularly high efficiency of RTX have been observed against lung disorders. No significant remission of granuloma infiltration in the orbits has been noted. Better evaluation of efficiency and safety of rituximab needs further evaluation.

Plasma exchange for induction and cyclosporine A for maintenance of remission in Wegener's granulomatosis--a clinical randomized controlled trial.

The use of plasma exchange (PE) for induction treatment of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV), including Wegener's granulomatosis (WG), is still controversial. The use of PE in AAV is not commonly accepted in patients with a plasma creatinine <500 μmol/L (5.7 mg/dL) despite experimental support for involvement of ANCA in the pathogenesis of vasculitis. In a single-centre study from a tertiary referral centre, 32 patients with ANCA-positive WG were treated with standard immunosuppressive therapy, prednisolone and cyclophosphamide (CYC). In addition, they were randomized to treatment with or without initial PE. After 3 months, they were further randomized in a Latin square design to continue CYC or to change to cyclosporine A (CyA) for 9 months. The renal follow-up was at least 5 years. Renal survival after 1, 3 and 12 months, and 5 years was significantly better in the PE groups. For all groups, the kidney/patient survival was 87.5%/93.7% at 1 year and 72%/56% at 5 years. All patients who were on dialysis when recruited were dialysis dependent 5 years later. There was no difference in morbidity or mortality between PE and control groups. Multivariate analysis demonstrated that PE improved renal survival (P < 0.01) at initial plasma creatinine levels >250 µmol/L (2.85 mg/dL). Change from CYC to CyA did not influence rate of relapses or time to relapse. PE is recommended for induction therapy in WG patients at creatinine levels >250 µmol/L (2.85 mg/dL), whereas previous randomized studies have limited PE to patients with creatinine >500 µmol/L (5.65 mg/dL).

Culture-negative subacute bacterial endocarditis masquerades as granulomatosis with polyangiitis (Wegener's granulomatosis) involving both the kidney and lung.

Subacute bacterial endocarditis (SBE) occasionally exhibits positive cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) of the anti-proteinase-3 (PR-3) type. Clinically, it mimics ANCA-associated vasculitis, such as Wegener's disease with glomerulonephritis. Lung abscesses are the most common manifestation of lung involvement. We herein report a case of culture-negative SBE strongly c-ANCA/PR3-positive accompanied by pulmonary involvement and glomerulonephritis. In this case, we took biopsies of both the lung and kidney, although renal biopsy is usually preferred over lung biopsy. The lung biopsy showed severe alveolar capillaritis, suggesting vasculitis consistent with polyangiitis. The renal biopsy revealed glomerulonephritis with a membranoproliferative pattern. To our knowledge, this is the first such reported case. A 68-year-old Chinese male patient presented to our hospital with a fever, cough, chest pain, and recurrent peripheral edema. He had a past medical history significant for treated schistosomiasis 20 years previously. Physical examination revealed palpable purpura, mild hypertension, hepatosplenomegaly, and a holosystolic cardiac murmur (Levine 2/6). Echocardiography showed tricuspid valve vegetations with moderate to severe regurgitation. Serum c-ANCA/PR3 and cryoglobulin were strongly positive. Renal biopsy results indicated membranoproliferative glomerulonephritis with several crescents. Chest CT revealed multiple intraparenchymal and subpleural nodules, and lung biopsy showed polyangiitis. The patient's ANCA titers, glomerulonephritis, and pulmonary injury all resolved after antibiotic therapy. SBE may present with positive c-ANCA/PR3, multiple pulmonary nodules, pulmonary polyangiitis, and glomerulonephritis clinically mimicking granulomatosis with polyangiitis (Wegener's granulomatosis).


We find a patient with hypoventilation. Glycemia is correct (we rule out hyperosmolar coma and hypoglycemia, option 2 and 4), so, although there is no history of intoxication, we have to go to the most frequent and that we can antagonize with antidotes: benzodiazepines (flumazenil) and opiates (naloxone). If we suspect ethylene glycol intoxication, we would administer thiamine, but there are no data to make us suspect.

We find a patient with hypoventilation. Glycemia is correct (we rule out hyperosmolar coma and hypoglycemia, [HIDDEN]), so, although there is no history of intoxication, we have to go to the most frequent and that we can antagonize with antidotes: benzodiazepines (flumazenil) and opiates (naloxone). If we suspect ethylene glycol intoxication, we would administer thiamine, but there are no data to make us suspect.

A 56-year-old patient is found comatose at home. He has a history of arterial hypertension and diabetes mellitus. He has no toxic habits or any other chronic disease. He is on treatment with irbesartan and empaglifozin. He shows no signs of malnutrition. His blood pressure is 110/60 mmHg, heart rate 110 bpm, 90% SatO2, capillary glucose 120 mg/dl and respiratory rate 7 rpm. Which initial therapeutic approach do you think is the most correct?

Administer naloxone, flumazenil and thiamine.

Administer naloxone, flumazenil and hypertonic glucose.

Administer thiamine and hypertonic glucose.

Coma cocktail

A coma cocktail is a combination of substances administered in an emergency to comatose individuals when the cause of the coma has not yet been determined. The intention is to work against various causes of a coma seen in an emergency setting including drug overdoses and hypoglycemia. A standard combination included dextrose (1 Amp D50W IV), flumazenil (0.2 mg IV), naloxone (2 mg IV), and thiamine (100 mg IV). It has been suggested that the use of naloxone and flumazenil be administered more selectively than glucose and thiamine. Some have proposed that the concept be abandoned completely because modern EMS providers should be able to determine the likely etiology of the change in mental status. At a minimum, the clinical presentation of the patient should rule in or out some portions of the coma cocktail. For example, with the advent and widespread implementation of glucometers, the indications for administering glucose can be more narrowly defined and its use more regimented.

Hypoglycemia

Treatment After hypoglycemia in a person is identified, rapid treatment is necessary and can be life-saving. The main goal of treatment is to raise blood glucose back to normal levels, which is done through various ways of administering glucose, depending on the severity of the hypoglycemia, what is on-hand to treat, and who is administering the treatment. A general rule used by the American Diabetes Association is the "15-15 Rule," which suggests consuming or administering 15 grams of a carbohydrate, followed by a 15-minute wait and re-measurement of blood glucose level to assess if blood glucose has returned to normal levels. Self-treatment If an individual recognizes the symptoms of hypoglycemia coming on, blood sugar should promptly be measured, and a sugary food or drink should be consumed. The person must be conscious and able to swallow. The goal is to consume 10-20 grams of a carbohydrate to raise blood glucose levels to a minimum of 70 mg/dL (3.9 mmol/L).

No more coma cocktails. Using science to dispel myths & improve patient care.

It should be clear from this discussion that coma cocktails are a bad idea and should be immediately abandoned. In fact, the indiscriminate use of the coma cocktail may indeed harm patients, EMS has evolved to a point where any EMS provider should be able to reasonably determine the most likely cause of coma, or, in a worst-case scenario, narrow the cause to but a few possibilities. Certainly, patients with bona fide hypoglycemia should receive IV glucose. Because the consequences of prolonged hypoglycemia are severe, if there's a doubt about whether hypoglycemia is present, then glucose should be empirically administered. Naloxone should be used only for those cases in which a narcotic overdose appears likely. Similarly thiamine administration should be limited to patients suspected of chronic alcohol abuse and who exhibit at least one of the three symptoms of WE described above. Flumazenil has no role in the routine treatment of coma unless the patient is known to not be benzodiazepine dependent and the overdose is known to result only from benzos--two very difficult requirements to verify in the back of an ambulance at 2 a.m. Coma cocktails are bad medicine. Let's banish them from our EMS armamentarium.

Coma cocktail

Dextrose If the blood glucose concentration of the patient is alternating consciousness or at least contributing to the alteration, said patient likely needs hypertonic dextrose. Another indicator is seizures. Hypertonic dextrose is effective in treating hypoglycemia, and one in twelve patients administered for altered mental status suffer from it. This statistic may be sufficient evidence for doctors to support the routine of administering the drug. Dextrose contributes to the controversy of coma cocktails by inducing Wernicke–Korsakoff syndrome in patients that are deficient in thiamine. Patients that are specifically at risk of being impacted this way are those with alcoholic tendencies or malnourishment.

Neurology_Adams

2. The management of shock, if present, takes precedence over all other diagnostic and therapeutic measures. 3. Concurrently, an intravenous line is established and blood samples are drawn for determination of glucose, intoxicating drugs, and electrolytes and for tests of liver and kidney function. Naloxone, 0.5 mg, should be given intravenously if a narcotic overdose is a possibility. Hypoglycemia that has produced stupor or coma requires the infusion of glucose, usually 25 to 50 mL of a 50 percent solution followed by a 5 percent infusion; this must be supplemented with thiamine. A urine sample is obtained for drug and glucose testing. If the diagnosis is uncertain, both naloxone and the glucose-thiamine combination should be administered.

Neurology_Adams

Many times the primary disorder underlying coma is perfectly obvious, as with severe cranial trauma or a known drug overdose. All too often, however, the comatose patient is brought to the hospital and little pertinent medical information is available. The need for efficiency in reaching a diagnosis and providing appropriate acute care demands that the physician have a methodical approach that first addresses the common and treatable causes of coma. When the comatose patient is first seen, the patient’s airway is cleared and blood pressure is restored; if trauma has occurred, one must check for bleeding from a wound or ruptured organ (e.g., spleen or liver). With hypotension, placement of a central venous line and administration of fluids and pressor agents, oxygen, blood, or glucose solutions (preferably after blood is drawn for glucose determinations and thiamine is administered) take precedence over diagnostic procedures. If respirations are shallow or labored, or if there is

Unconscious Patient -- Treatment / Management

Circulation: A mean arterial blood pressure below 70 mm Hg should be treated with fluids or vasopressors. Mean arterial pressures exceeding 130 mm Hg may require administering intravenous (IV) labetalol at a dose of 5 to 20 mg or as necessary. Vital Signs: The vital signs of an unconscious patient should be obtained if this task has not yet been completed. Glucose Administration: If the cause of the coma is unknown, 25 g of dextrose should be administered while awaiting the results of laboratory tests. Thiamine Administration: In cases of malnourishment, a 100 mg dose of thiamine should be administered alongside or before administering glucose to the patient.

Pharmacology_Katzung

Ramin Sam, MD, Harlan E. Ives, MD, PhD, & David Pearce, MD A 65-year-old man has a history of diabetes and chronic kidney disease with baseline creatinine of 2.2 mg/dL. Despite five different antihypertensive drugs, his clinic blood pres-sure is 176/92 mm Hg; he has mild dyspnea on exertion and 2–3+ edema on exam. He has been taking furosemide 80 mg twice a day for 1 year now. At the clinic visit, hydrochlorothi-azide 25 mg daily is added for better blood pressure control and also to treat symptoms and signs of fluid overload. Two weeks later, the patient presents to the emergency depart-ment with symptoms of weakness, anorexia, and generalized malaise. His blood pressure is now 91/58 mm Hg, and he has lost 15 kg in 2 weeks. His laboratory tests are signifi-cant for a serum creatinine of 10.8 mg/dL. What has led to the acute kidney injury? What is the reason for the weight loss? What precautions could have been taken to avoid this hospitalization?

Just the Facts: Diagnosis and treatment of diabetic ketoacidosis in the emergency department.

A 21-year-old male with known type 1 diabetes mellitus presented to the emergency department (ED) with two days of vomiting, polyuria, and polydipsia after several days of viral upper respiratory tract infection symptoms. Since his symptom onset, his home capillary blood glucose readings have been higher than usual. On the day of presentation, his glucometer read "high," and he could not tolerate oral fluids. On examination, his pulse was 110 beats/minute, and his respiratory rate was 24 breaths/minute. He was afebrile, and the remaining vital signs were normal. Other than dry mucous membranes, his cardiopulmonary, abdominal, and neurologic exams were unremarkable. Venous blood gas demonstrated a pH of 7.25 mm Hg, pCO2 of 31 mm Hg, HCO3 of 13 mm Hg, anion gap of 18 mmol/L, and laboratory blood glucose of 40 mmol/L, as well as serum ketones measuring "large."

R v Quick

Such malfunctioning of his mind as there was, was caused by an external factor and not by a bodily disorder in the nature of a disease which disturbed the working of his mind. It follows in our judgment that Quick was entitled to have his defence of automatism left to the jury and that Mr. Justice Bridge's ruling as to the effect of the medical evidence called by him was wrong. Had the defence of automatism been left to the jury, a number of questions of fact would have had to be answered. If he was in a confused mental condition, was it due to a hypoglycaemic episode or to too much alcohol? If the former, to what extent had he brought about his condition by not following his doctor's instructions about taking regular meals? Did he know that he was getting into a hypoglycaemic episode? If yes, why did he not use the antidote of eating a lump of sugar as he had been advised to do? On the evidence which was before the jury Quick might have had difficulty in answering these questions in

Opioid Toxicity -- Differential Diagnosis

If the classic signs of opioid toxicity are present in a comatose patient, such as constricted pupils and slow respiratory rate, assumptions are often that there is nothing else this patient could have. If after naloxone reversal, the patient appears to have normalized, this assumption can be justified. However, undifferentiated comatose patients are often seen in the emergency setting and can be challenging to evaluate and treat. Traditionally, a "coma cocktail" of 4 medications (dextrose/thiamine/naloxone/flumazenil) was used, but only one of the components of the original cocktail (naloxone) remains in use in emergency care as of early 2019. [26] Sometimes an unforeseen consequence of injecting a robust dose of naloxone into the undifferentiated comatose patient is subsequent agitation, which can at times severely limit the team's efforts to evaluate for potentially severe underlying disease unrelated to opioid toxicity. It is often best to consider a very small test dose of naloxone such as 0.4 mg intravenous in the adult patient if that medication is to be given diagnostically and to keep the differential broad regarding potential etiologies of unresponsiveness until the history and physical findings narrow that differential.

Neurology_Adams

We have had the success with the following program, which reflects several published approaches. When the patient is first seen, an initial assessment of cardiorespiratory function is made and an oral airway established. As summarized by Bleck, a large-bore intravenous line is inserted; blood is drawn for glucose, BUN, electrolytes, and a metabolic and drug screen. A normal saline infusion is begun and a bolus of glucose is given (with thiamine if malnutrition and alcoholism are potential factors). To rapidly suppress the seizures, we generally use diazepam intravenously at a rate of about 2 mg/min until the seizures stop or a total of 20 mg has been given; alternatively, lorazepam, 0.1 mg/kg given by intravenous push at a rate not to exceed 2 mg/min, is now favored, being marginally more effective than diazepam because of its clinically longer duration of action (see Table 15-8).

Central nervous system depression

There are two antidotes that are frequently used in the hospital setting and these are naloxone and flumazenil. Naloxone is an opioid antagonist and reverses the central nervous depressive effects seen in opioid overdose. In the setting of a colonoscopy, naloxone is rarely administered but when it is administered, its half-life is shorter than some common opioid agonists. Therefore, the patient may still exhibit central nervous system depression after the naloxone has been cleared. Naloxone is typically administered in short intervals with relatively small doses in order to prevent the occurrence of withdrawal, pain, and sympathetic nervous system activation. Flumazenil is a benzodiazepine antagonist and blocks the binding of benzodiazepines to gamma-aminobutyric acid receptors. Similarly to naloxone, flumazenil has a short half-life, and this needs to be taken into account because the patient may exhibit central nervous depression after the antidote has been cleared. Benzodiazepines

Coma cocktail

Naloxone Naloxone effectively treats CNS and respiratory depression caused by opiate/opioid overdose. It allows adequate ventilation for impacted patients, and health professionals administer it intravenously. Naloxone has well-documented effectiveness; as a matter of fact, 575/609 patients (mainly with heroin overdose) showed improved consciousness and respiration within five minutes of treatment. The major downsides to naloxone are the hypersensitivity from the patient and its reaction with substances contaminating opioids/opiates. In terms of hypersensitivity, the patient may subsequently suffer from restlessness, headache, and vomiting. Opiates/opioids, such as heroin, can be contaminated with scopolamine, and if it is present, the patient may face an anticholinergic crisis. Flumazenil Flumazenil is an imidazobenzodiazepine that can help mediate and antagonize the effects of benzodiazepines. It can be used in anaesthesia as well as intensive care.

Demystifying hypoglycemia. When is it real and how can you tell?

Contrary to popular belief, hypoglycemia is an infrequently encountered condition and its presence is questionable until confirmed by appropriate tests. In ambulatory patients, blood glucose levels obtained during intake of a normal diet are more reliable than those obtained during a glucose tolerance test. If the blood glucose is actually abnormally low and the other two criteria of hypoglycemia are also satisfied, a search for the cause is in order. In hospitalized patients, excessive doses of insulin or oral hypoglycemic agents, the effect of drugs, or chronic renal failure are the most common causes of hypoglycemia. If these factors are absent, another chronic illness known to cause hypoglycemia may be the source. If the cause is still obscure, a thorough evaluation of the endocrine status is warranted.

A case report of opium body packer; review of the treatment protocols and mechanisms of poisoning.

ABSTRACT Body packers are people who illegally carry drugs, mostly cocaine as well as opium and/or heroin, concealed within their bodies. The packets are inserted in the mouth, rectum, or vagina in order to get across borders without being detected. In this presentation we report a case of an opium body packer and review the available scientific literature by focusing on mechanisms of toxicity and treatment approach. The patient was a 35-year-old man who had lethargy, respiratory depression, tachycardia, normal blood pressure, hyperthermia, and pinpoint pupils on presentation. No past medical history was obtained and the only positive history was his travel from Afghanistan 2 days earlier, which he had given to emergency personnel before arriving at our hospital. Complete blood cells and kidney and liver tests were all in normal range. In the emergency department, the patient was treated with oxygen, naloxone, and hypertonic glucose. One dose of activated charcoal (1 g/kg) was administered orally. After intravenous injection of naloxone (4 mg), the lethargy, respiratory depression, and miosis were resolved. The patient was admitted to the intensive care unit and 90 min after admission, the patient redeveloped respiratory distress and lost consciousness. He was intubated and mechanically ventilated due to the suspicious of body packing. Plain abdominal x-ray showed multiple packets throughout the gastrointestinal tract; 81 packets were removed by surgery and three of them were left due to leaking. After removing the packets, the patient was treated conservatively. He suffered a pulmonary infection (aspiration pneumonia) and he regained consciousness after 4 days. Upon recovery the patient was seen by a psychiatrist prior to going to prison. Surgery is recommended for body packers who have significant signs or symptoms.

[What lies under the glass on the medical professional's table?].

Normal values are intervals covering the majority of cases detected in healthy individuals. They are gradually replaced by diagnostic criteria based on probability of differentiation between the healthy and ill (prognostic intervals). In 1970-ies, "recommended for health promotion" intervals appeared. The physician must know the origin of the criteria recommended for assessment of the results of the laboratory test or another measurement, in diagnosis, only diagnostic criteria must be used but not criteria designed for prophylactic programs. In the context of each disease diagnostic criteria should account for possible sequelae. Such criteria are multiple: for one test (e.g. plasma glucose concentration) there are different criteria for diagnosis of different diseases (diabetes type 1 or 2, hypothyroidism). Only such criteria should be included in recommendations (standards) on diagnosis and treatment of certain diseases. Conventional "normal values" should be used only in assessment of the results of prophylactic surveys and in search for explanation for the obscure states.

Unconscious man in his fifties with elevated anion gap.

The use of GHB is still widespread with many hospitalised overdose cases. A man in his fifties was found unconscious in the street and brought to our Acute Admissions. When first examined he was still unconscious, hypothermic, had snoring respiration and smelled of alcohol. He was otherwise haemodynamically stable. Blood samples showed elevated osmolal and anion gaps. The increase in the osmol gap could be explained by the ethanol level of 210 mg/dL (46 mmol/L), but the reason for the increased anion gap was unknown. Flumazenil and naloxone were administered without effect. As the ethanol concentration alone was unlikely to explain the clinical picture, extended toxicological tests were performed. GHB in plasma was very high (5.0 mmol/L; 520 mg/L) even though the sample was taken almost 4 hours after admission. The GHB concentration (present as an anion) corresponded to the increased anion gap. The patient was comatose for approximately 12 hours, which is unusually long in GHB poisoning. Intoxication with GHB is important to consider in comatose patients where other causes are excluded. Prolonged clinical course may be due to a saturation of the GHB metabolism after a large dose or ingestion of GBL or 1,4-butanediol, both of which are precursors to GHB.

[CME/Answers: Metformin - Dos and Don'ts].

CME/Answers: Metformin - Dos and Don'ts <bAbstract.</b CME/Answers: Metformin - Dos and Don'ts In the absence of contraindications metformin is still considered the initial medication in patients with diabetes mellitus type 2, although diabetes therapy is rapidly changing. Metformin is used both as monotherapy and in combination with any other diabetic medication. As a biguanide metformin improves glycemic control by inhibiting gluconeogenesis and increasing insulin-mediated glucose utilization in peripheral tissues. Metformin promotes modest weight reduction and provides several other advantages: no risk of hypoglycemia, excellent general tolerability, well-known long-term safety profile and low-cost. The most common gastrointestinal side effects are usually mild and transient, but vitamin B12 deficiency may develop. Metformin-associated lactic acidosis (MALA) is a rare, but relevant and life-threatening complication. The risk increases with renal impairment; therefore the metformin dose must be adjusted to the eGFR. The use of metformin is contraindicated with an eGFR <30 ml/min/1.73 m2. There are other contraindications: concurrent active or progressive severe liver disease, active alcohol abuse, unstable or acute heart failure, hypoperfusion and hemodynamic instability, as well as a past history of lactic acidosis. Since metformin remains a modern therapy, it is important to be aware of its indications and contraindications.

Neurology_Adams

It must be emphasized, as it was in Chap. 40, that a special danger attends the use of glucose solutions in alcoholic patients. The administration of intravenous glucose may serve to consume the last available reserves of thiamine and precipitate Wernicke disease. Typically, these patients have subsisted on a diet disproportionately high in carbohydrate (in addition to alcohol, which is metabolized entirely as carbohydrate) and low in thiamine, and their body stores of B vitamins may have been further reduced by gastroenteritis and diarrhea. For this reason it is good practice to add B vitamins, specifically thiamine (which may also be supplemented by intramuscular injection), in all cases requiring parenterally administered glucose—even though the alcoholic disorder under treatment, for example, delirium tremens, is not primarily caused by vitamin deficiency.

The poisoned patient with altered consciousness. Controversies in the use of a 'coma cocktail'.

In the assessment and management of the potentially poisoned patient with altered consciousness, the most consequential and controversial interventions occur during the first 5 minutes of care. In this review article, the risks and benefits of standard diagnostic and therapeutic interventions are presented to guide clinicians through this critical period of decision making. Data for discussion were obtained from a search of English-language publications referenced on MEDLINE for the years 1966 to 1994. Older literature was included when pertinent. Search terms included poisoning, overdose, toxicity, naloxone, glucose, thiamine, and flumazenil. Only large trials were used for determinations of diagnostic utility and efficacy. Small trials, case series, and case reports were reviewed extensively for adverse effects. Trials were reviewed for overall methodology, inclusion and exclusion criteria, sources of bias, and outcome. Analysis favors empirical administration of hypertonic dextrose and thiamine hydrochloride to patients with altered consciousness. Although rapid reagent test strips can be used to guide this therapy, they are not infallible, and they fail to recognize clinical hypoglycemia that may occur without numerical hypoglycemia. Administration of naloxone hydrochloride should be reserved for patients with signs and symptoms of opioid intoxication. Flumazenil is best left for reversal of therapeutic conscious sedation and rare select cases of benzodiazepine overdose.

21 grams experiment

Experiment In 1901, Duncan MacDougall, a physician from Haverhill, Massachusetts, who wished to scientifically determine if a soul had weight, identified six patients in nursing homes whose deaths were imminent. Four were suffering from tuberculosis, one from diabetes, and one from unspecified causes. MacDougall specifically chose people who were suffering from conditions that caused physical exhaustion, as he needed the patients to remain still when they died to measure them accurately. When the patients looked like they were close to death, their entire bed was placed on an industrial sized scale that was sensitive within two tenths of an ounce (5.6 grams). On the belief that humans have souls and that animals do not, MacDougall later measured the changes in weight from fifteen dogs after death. MacDougall said he wished to use dogs that were sick or dying for his experiment, though was unable to find any. It is therefore presumed he poisoned healthy dogs.

Case files of the University of Massachusetts fellowship in medical toxicology: lethal dose of opioids contained in an elastomeric capsule labeled as vancomycin.

A 67 year-old male presented to the emergency department with alteration in mental status. On arrival he had vital signs: pulse 110, BP 173/83, respiratory rate 4, oxygen saturation 57% and temperature 36.1 degrees Celsius. His past medical history included hypertension, vitamin B12 deficiency, hyperlipidemia, and recurrent cellulitis treated with vancomycin. The patient had no response to noxious stimuli, pinpoint pupils, and agonal respirations. Secondary to his wife's vehement denial that he had access to or history of using any narcotics, he was intubated after 2.2mg IV naloxone failed to reverse respiratory depression. Thirty minutes before presentation, however, he had received an intravenous infusion of vancomycin administered by his wife at home. The vancomycin, obtained from a home infusion medication supply company, was contained in one of five sealed elastomeric capsules delivered earlier that day. A qualitative comprehensive toxicology screen of urine for 1043 substances identified morphine, codeine, naloxone, lidocaine and caffeine. The original elastomeric container was not available for testing, but another container from the same delivery was submitted for testing to the state forensic laboratory. This intact container was labeled as Vancomycin 1g in 240mL of normal saline. The forensic laboratory confirmed that the alkaloidal contents of the elastomeric capsule were 10% codeine, 4.4% 6-monoacetyl morphine, and 84% morphine. No vancomycin was identified in the infusion bottles. The case was referred to the local police department and the state department of health drug control board. The home infusion company was also immediately notified to prevent similar occurrence. We are reporting the first known case of opioid overdose from an adulterated elastomeric capsule that was labeled as containing an antimicrobial agent.

[The effects of flumazenil or bicuculline on the respiratory depression by morphine].

The effects of intravenous administration of flumazenil (n = 6) or bicuculline (n = 6) on the discharge of the phrenic nerve were studied following vagotomy in pentobarbital anesthetized mechanically ventilated rats. Morphine (0.4 mg.kg-1.min-1) was administrated until the respiratory rate decreased to about a half of the baseline respiratory rate. In this state, we first administered flumazenil (0.25 mg.kg-1) or bicuculline (0.4 mg.kg-1), intravenously and then administered naloxone (0.02 mg) intravenously in the two groups. The increase of inspiratory time from 0.7 +/- 0.1 to 2.0 +/- 0.5 s by morphine recovered to 0.8 +/- 0.2 s by bicuculline and to 0.6 +/- 0.1 s by naloxone. The increase of inspiratory time from 0.7 +/- 0.1 to 1.7 +/- 0.3 s by morphine, and to 2.1 +/- 0.5 s by flumazenil recovered to 0.6 +/- 0.1 s by naloxone. Expiratory time did not change during each drug administration in the two groups. The decrease of respiratory rate from 44 to 23 +/- 4 breaths.min-1 by morphine recovered to 37 +/- 5 breaths.min-1 by bicuculline and to 42 +/- 2 breaths.min-1 by naloxone. The decrease of respiratory rate from 45 +/- 3 to 22 +/- 6 breaths.min-1 by morphine, and to 18 +/- 4 breaths.min-1 by flumazenil recovered to 46 +/- 3 breaths.min-1 by naloxone. Amplitude of integrated phrenic nerve discharge increased to 125 +/- 42% by bicuculline and to 175 +/- 93% by naloxone compared to the baseline values. The decrease of amplitude to 54 +/- 18% by flumazenil recovered to 125 +/- 42% by naloxone. These results suggest that bicuculline not flumazenil antagonizes the respiratory depression of morphine by increasing the respiratory rate and respiratory movement.

[Non-fatal hyperkalemia in lactic acidosis due to metformin overdose. Report of one case].

We report a 74-year-old man with diabetes mellitus type 2 and hypertension, who recently underwent coronary bypass surgery due to severe triple vessel disease receiving cardiological and combined antidiabetic therapy, including metformin 4 g/day. He was admitted with abdominal pain, nausea, vomiting, diarrhea and loss of consciousness. At admission, he was disoriented and agitated with signs of poor perfusion. His blood pressure was 80/70 mmHg, pulse rate 40 beats/min, respiratory rate 20-breaths/min, and axillary temperature 35 °C. Biochemical profile revealed an extreme hyperkalemia of 15.4 mEq/L (double checked), elevated creatinine, uremia and brain natriuretic peptide; hypoglycemia (blood glucose 68 mg/dl) and normal C Reactive Protein. Arterial blood gases revealed severe lactic acidemia. The electrocardiogram showed sinus bradycardia, simple AV block, widened QRS with prominent T wave and prolonged QT. He was admitted to the Intensive Care Unit (ICU) with the suspicion of lactic acidosis associated with metformin, receiving fluid management, intravenous hypertonic glucose plus insulin and sodium bicarbonate, mechanical ventilation, vasopressor therapy, a temporary pacemaker lead, in addition to continuous venovenous hemodiafiltration. Two days later, the patient experienced a significant clinical improvement with normalization of the acid-base status, plasma lactate and potassium levels. On day 9, diuresis was recovered, creatinine and uremia returned to normal levels and the patient was discharged from the ICU.

[On proportionate medical actions and extraordinary methods of treatment].

As a general rule, any medical action should be proportionated. That is, the expected benefit of the treatment provided must be commensurate to the diagnosis and prognosis, the therapeutic efforts the suffering caused to the patient, and the eventual risks. Inversely a disproportionate or excessive medical action that will result in no benefit to the patient is technically incorrect and ethically reprebensible. As opposed to ordinary methods of treatment (basic nursing, feeding, hydration, drugs and regular clinical procedures), we reserve the name of "extraordinary methods of treatment" to those medical actions using complex and invasive highcost procedures and equipment that should be urgently indicated in any critically ill patient with a potentially reversible disease. These do not have any indication in terminally ill patients, except in the case of concomitant potentially reversible acute complications. When a DNR (do not resuscitate) order is adopted it should be reassessed periodically. The use, withholding and withdrawal of these extraordinary measures of treatment are subject to a series of medical and ethical requirements, which receive full discussion in this paper.

[Antagonism of flunitrazepam and fentanyl by flumazenil, naloxone or nalbuphine].

The new benzodiazepine antagonist flumazenil represents another approach to the ever-present problem of recurring respiratory depression after anesthesia with flunitrazepam and fentanyl. Objective and subjective side effects of flumazenil were studied in comparison with the opiate antagonists naloxone and nalbuphine. METHODS. One hundred fifty surgical patients, ASA I or II, aged 18-65 years were studied. After premedication with atropine 0.5 mg and flunitrazepam 0.5 mg anesthesia was induced with flunitrazepam 0.5 mg, fentanyl 0.1 mg and etomidate 10 mg and maintained with N2O/O2 2:1 and additional increments of 0.1 mg fentanyl as required. Relaxation for intubation and surgery was obtained with non depolarizing muscle relaxants. After the operation the patients were extubated and then flumazenil 0.4 mg, naloxone 0.05 mg, or nalbuphine 20 mg was given i.v. (randomized and double-blind). In 15 patients blood pressure and heart rate were monitored. In all patients postoperative pain was assessed by the time interval between administration of the antagonist and need for the first analgesic medication. On the 1st postoperative day recall of postoperative events and of pictures shown 5, 30, 60, 120, and 240 min after administration of the antagonist was tested. The patients were interviewed a second time for side effects on day 3-6 after the operation. RESULTS. The three antagonists produced no significant effects on arterial pressure and heart rate. There were no differences between the antagonists in the incidence of postoperative nausea and/or vomiting or postoperative pain. After flumazenil, a significant transient increase in vigilance and better recall of postoperative events was noted within 5 and 30 min after administration of the drug. CONCLUSION. On the basis of the objective clinical findings, there is no reason to prefer either benzodiazepine or opiate antagonists after flunitrazepam and fentanyl. However, postoperative amnesia can be reduced by flumazenil if this is desirable.

Metformin-associated respiratory alkalosis.

We present an 84-year-old man with a history of chronic obstructive pulmonary disease, type 2 diabetes, hypertension, glaucoma, and bladder cancer who presented to the emergency department after the police found him disoriented and confused. Metformin therapy began 3 days before, and he denied any overdose or suicidal ideation. Other daily medications included glipizide, fluticasone, prednisone, aspirin, furosemide, insulin, and potassium supplements. In the emergency department, his vital signs were significant for hypertension (168/90), tachycardia (120 bpm), and Kussmaul respirations at 24 breaths per minute. Oxygen saturation was 99% on room air, and a fingerstick glucose was 307 mg/dL. He was disoriented to time and answered questions slowly. Metformin was discontinued, and by day 3, the patient's vital signs and laboratory test results normalized. He has been asymptomatic at subsequent follow-up visits. Metformin-associated lactic acidosis is a well-known phenomenon. Respiratory alkalosis may be an early adverse event induced by metformin prior to the development of lactic acidosis.

[Management of the drunken patient].

Acute ethanol intoxication is frequent in emergency departments. The clinical presentation is highly variable and ranges from an inebriety to a coma and sometimes an agitated patient. You have to examine completely the patient and to do complementary exams with a capillary glycemia as the minimal standard. We must keep in mind that an acute ethanol intoxication is a diagnosis of exclusion. With trauma patients, we have to keep a low threshold for asking radiological advanced imaging, like cerebro-cervical CT scan. The patient should be reexamined frequently. The treatment is a supportive one. If the patient is agitated, you can give him haloperidol or a benzodiazepine. Before discharge, the patient should see the alcohologic team.

Octreotide therapy for recurrent refractory hypoglycemia due to sulfonylurea in diabetes-related kidney failure.

To describe a patient with kidney insufficiency from diabetes treated with glyburide, who presented with prolonged and recurrent hypoglycemia unresponsive to large intravenous doses of glucose, which was treated successfully with intravenously administered octreotide, and to review the therapeutic options for hypoglycemia. We present a case report of a 66-year-old man with diabetes causing chronic kidney disease, who was treated with orally administered glyburide, 7.5 mg twice a day. He initially presented to another hospital because of hypoglycemia and was treated with intravenously administered glucose and discharged. The next day, his family brought him to our emergency department because of recurring low blood glucose levels and symptoms of sweating, fever, and nightmares. Laboratory tests revealed a blood glucose level of 33 mg/dL and a creatinine concentration of 6.2 mg/dL. The patient was treated with a 5% dextrose and, subsequently, a 10% dextrose infusion without any sustained improvement. The blood glucose level remained low despite the additional administration of 3 ampules of 50% dextrose in water. The patient was given a bolus of octreotide (50 mug subcutaneously) 14 hours after his second presentation. He received another 50-mug dose of octreotide 6 hours later. After this bolus, the hypoglycemia resolved, and he no longer required intravenous administration of glucose to maintain euglycemia. Patients with diabetes and kidney disease frequently have persistent and difficult-to-treat hypoglycemia, unresponsive to conventional therapy. Octreotide is an effective and safe treatment for patients with refractory hypoglycemia attributable to sulfonylureas.

Effect of flumazenil on basal and naloxone-stimulated ACTH and cortisol release in humans.

1. Endogenous benzodiazepine receptor ligands are thought to influence the human hypothalamic-pituitary-adrenal (HPA) axis and naloxone, a known stimulator of adrenocorticotropic hormone (ACTH) release, is thought to act via release of hypothalamic corticotropin-releasing hormone. 2. The aim of the present study was to assess the influence of endogenous benzodiazepine-receptor ligands by administering flumazenil (Ro15-1788), a benzodiazepine antagonist, and measuring ACTH and cortisol release, both basal and during naloxone-stimulation. 3. Nine normal volunteers in a placebo-controlled double-blind design were studied. Flumazenil (0.5 mg, i.v. bolus) was given 2 min before naloxone (125 micrograms/kg bodyweight, i.v. bolus) immunoreactive-adrenocorticotropic hormone (IR-ACTH) and cortisol levels were measured at frequent intervals from 60 min before to 120 min after naloxone injection. 4. Flumazenil had no effect on ACTH and cortisol release when given alone; flumazenil area under the ACTH/time curve (pmol/L.min) = -36.5 +/- 63.5 compared with placebo = -53.5 +/- 31.8, flumazenil area under the cortisol/time curve (nmol/L.min x 10(-3)) = - 2.4 +/- 2.4 compared with placebo -0.56 +/- 1.4. Flumazenil did not change the ACTH and cortisol release achieved with naloxone; naloxone area under the ACTH/time curve (pmol/L.min) = 327.8 +/- 61.7 compared with flumazenil/naloxone = 366.3 +/- 88.1, naloxone area under the cortisol/time curve (nmol/L. min x 10(-3) = 12.2 +/- 3.4 compared with naloxone/flumazenil = 10.5 +/- 2.1. 5. The authors conclude that flumazenil dose not modify basal or stimulated ACTH and cortisol release in healthy humans. This would suggest that endogenous benzodiazepine-like ligands and the benzodiazepine/gamma-aminobutyric acid receptor complex do not tonically influence the hypothalamic-pituitary-adrenal axis.

Altered level of consciousness

Treatment Treatment depends on the degree of decrease in consciousness and its underlying cause. Initial treatment often involves the administration of dextrose if the blood sugar is low as well as the administration of oxygen, naloxone and thiamine. See also Altered state of consciousness Disorders of consciousness Level of consciousness (esotericism) Cognitive deficit References External links Neuroscience Intensive care medicine Emergency medicine Central nervous system disorders Symptoms and signs of mental disorders Consciousness