Howard L. Corwin

Progression and Remission of Renal Disease in the Lupus Nephritis Collaborative Study: Results of Treatment with Prednisone and Short-term Oral Cyclophosphamide

OBJECTIVE To describe the clinical course of severe lupus nephritis and to identify the risk factors for progression to renal failure among patients treated with prednisone and short-term courses of low-dose oral cyclophosphamide. DESIGN Ancillary analyses of data from the Lupus Nephritis Collaborative Study (LNCS). SETTING University hospital medical centers (14). PATIENTS The 86 patients who participated in the LNCS (mean follow-up, 136 weeks [2.6 years]) and a subgroup of 63 patients with follow-up of more than 48 weeks (mean follow-up, 160 weeks [3.1 years]). MEASUREMENTS Initial clinical and pathologic features, response to therapy within 48 weeks, and subsequent clinical events, including development of renal failure. MAIN RESULTS Renal failure developed in 18 patients (21%). An observed elevation in serum creatinine concentration was the only initial feature predictive of subsequent renal failure. Mean (+/- SD) initial serum creatinine levels were higher in patients who subsequently developed renal failure (244 +/- 134 mumol/L [2.76 +/- 1.52 mg/dL] compared with 163 +/- 103 mumol/L [1.85 +/- 1.17 mg/dL]; P = 0.007). The risk for renal failure was higher among patients with initial serum creatinine levels greater than 106 mumol/L (1.2 mg/dL) (29% compared with 6.5%; P = 0.014). Response to therapy (defined as resolution of initial serum creatinine elevations within 48 weeks) refined the prognosis based on initial serum creatinine determinations. The risk for subsequent renal failure was higher among patients who failed to respond to therapy within 48 weeks (30% compared with 0%; P = 0.015). By comparison, 9% of patients with normal initial serum creatinine levels progressed to renal failure after 48 weeks. CONCLUSIONS Initial serum creatinine levels and responses to initial therapy with prednisone and short-term cyclophosphamide, as used in the LNCS, can guide further therapy. Patients with normal initial serum creatinine levels or resolution of initial serum creatinine elevations within 48 weeks have a low risk for renal failure and may not require long-term treatment with cyclophosphamide.

Efficacy of blood transfusion in the critically ill: Does age of blood make a difference?

Anemia is prevalent in critically ill patients, and recent studies well document that this results in large numbers of red blood cell (RBC) transfusions being given to treat the anemia in these critically ill patients (1, 2). By intensive care unit day 3, 95% of critically ill patients are anemic, and 40% to 50% of these patients received, on average, almost five units of RBCs during their intensive care unit stay (3). Blood loss, inappropriately low endogenous erythropoietin production, reduced red cell lifespan, reduced iron availability, and inhibition of erythropoiesis by cytokines and the inflammatory response all contribute to the anemia of critical illness (4) Despite the frequency of RBC transfusion in the critically ill, the optimal treatment of anemia in euvolemic critically ill patients remains controversial. During the last decade, the routine use of RBC transfusion for the treatment of anemia in critically ill patients has been scrutinized (3– 8). Little data exist supporting the efficacy of RBC transfusion, and recent data suggest that a more liberal transfusion practice may, in fact, result in worse clinical outcomes in some critically ill patients (3, 5– 8). It is not clear whether the adverse effects of RBC transfusion are a result of factors related to the RBC transfusion itself or a higher hemoglobin level. However, studies by Marik and Sibbald (9) and Fitzgerald et al. (10) have raised the question that transfusion of “older” ( 14 days) stored RBCs may be associated with adverse clinical effects. This is an important clinical question because the average age of RBCs transfused in the critically ill is 21 days, with almost 40% being 28 days old (3). If old cells are indeed a problem and should not be used, this would have a major impact on an already stressed blood supply system. In this issue of Critical Care Medicine, Walsh and colleagues (11) report the results of a prospective, randomized, double-blind pilot study aimed at investigating the effects of transfusion of two units of “fresh” ( 5 days) or “stored” ( 20 days) prestorage leukodepleted and plasma-depleted red blood cells in ventilated euvolemic critically ill patients (n 22) with anemia (hemoglobin concentration 9 g/dL). They determined that at 5 hrs, neither “fresh” nor “stored” RBC transfusions were associated with an improvement in tissue oxygenation as measured by automated gas tonometry. Furthermore, no adverse effect of “stored” red blood cell transfusion was identified in this study using the study outcome measures of pHi, Pg-PaCO2 gap, lactate, and base deficit. This is an important study that further extends our knowledge regarding the lack of efficacy of RBC transfusion for the treatment of anemia in critically ill patients. There are, however, some significant limitations to this single-center trial that should be noted. The authors stated that they enrolled euvolemic patients, but did not specify how they determined that the study patients were euvolemic. In fact, they defined a pHi of 7.35 as abnormal, and both study cohorts had abnormal pHi and high arterial lactate concentrations at baseline. Furthermore, the decision for RBC transfusion was at the treating physician’s discretion rather than any objective criteria. The study group was not homogeneous and included both surgical and medical patients and those with and without infection at time of study entry. There was also no evidence that these patients were, in fact, “delivery dependent.” The sample size was small, and there was considerable variability in intensive care unit length of stay at study entry, ranging from 2 to 22 days. The outcome measures in this study included regional and global indices of tissue oxygenation. Regional tissue oxygenation was measured by gastric tonometry indices of gastric mucosal oxygenation before, during, and after RBC transfusion. Global indices of tissue oxygenation were measured by serial lactate and base deficit. The variables were measured at 5 hrs, however it is unclear whether results would have been similar several hours later after the complete recovery of 2, 3 diphosphoglyceric acid. This study also did not assess other important more long-term outcome variables in critically ill patients, such as nosocomial infection and multiple organ failure (measured only at baseline in this study). Other studies have documented that RBC transfusion is an independent risk factor for nosocomial infection and multiple organ failure (11–18), although the use of leukodepleted RBC in this study may mitigate this risk (19). In stored blood preparations, it has been documented that free hemoglobin and polymorphonuclear leukocyte elastase concentrations increase significantly with storage time, with resultant increased hemolysis of RBCs (20). A recent hypothesis has emerged regarding the adverse effects of transfusion of stored blood. Cell-free ferrous hemoglobin in the plasma, after transfusion of stored blood, rapidly destroys nitric oxide by oxidation to methemoglobin and nitrate. Nitric oxide reacts at least 1,000 times more rapidly with free hemoglobin than with erythrocytes. Limited nitric oxide bioavailability promotes regional and systemic vasoconstriction and subsequent organ dysfunction (21, 22). In their current study, Walsh and colleagues (11) did not evaluate for these potential adverse effects associated with the transfusion of stored blood. Although prestorage leukoreduced blood was utilized in this study, it should be recognized that this only reduces the number of donor leukocytes infused from approximately 10 to 10 white blood cells per unit of blood (23). *See also p. 364. Copyright

Roundtable Debate: Controversies in the Management of the Septic Patient--Desperately Seeking Consensus

Despite continuous advances in technologic and pharmacologic management, the mortality rate from septic shock remains high. Care of patients with sepsis includes measures to support the circulatory system and treat the underlying infection. There is a substantial body of knowledge indicating that fluid resuscitation, vasopressors, and antibiotics accomplish these goals. Recent clinical trials have provided new information on the addition of individual adjuvant therapies. Consensus on how current therapies should be prescribed is lacking. We present the reasoning and preferences of a group of intensivists who met to discuss the management of an actual case. The focus is on management, with emphasis on the criteria by which treatment decisions are made. It is clear from the discussion that there are areas where there is agreement and areas where opinions diverge. This presentation is intended to show how experienced intensivists apply clinical science to their practice of critical care medicine.