Ronald G. Pearl

The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States.

ObjectiveTo quantify the incidence of anemia and red blood cell (RBC) transfusion practice in critically ill patients and to examine the relationship of anemia and RBC transfusion to clinical outcomes. DesignProspective, multiple center, observational cohort study of intensive care unit (ICU) patients in the United States. Enrollment period was from August 2000 to April 2001. Patients were enrolled within 48 hrs of ICU admission. Patient follow-up was for 30 days, hospital discharge, or death, whichever occurred first. SettingA total of 284 ICUs (medical, surgical, or medical-surgical) in 213 hospitals participated in the study. PatientsA total of 4,892 patients were enrolled in the study. Measurements and Main ResultsThe mean hemoglobin level at baseline was 11.0 ± 2.4 g/dL. Hemoglobin level decreased throughout the duration of the study. Overall, 44% of patients received one or more RBC units while in the ICU (mean, 4.6 ± 4.9 units). The mean pretransfusion hemoglobin was 8.6 ± 1.7 g/dL. The mean time to first ICU transfusion was 2.3 ± 3.7 days. More RBC transfusions were given in study week 1; however, in subsequent weeks, subjects received one to two RBC units per week while in the ICU. The number of RBC transfusions a patient received during the study was independently associated with longer ICU and hospital lengths of stay and an increase in mortality. Patients who received transfusions also had more total complications and were more likely to experience a complication. Baseline hemoglobin was related to the number of RBC transfusions, but it was not an independent predictor of length of stay or mortality. However, a nadir hemoglobin level of <9 g/dL was a predictor of increased mortality and length of stay. ConclusionsAnemia is common in the critically ill and results in a large number of RBC transfusions. Transfusion practice has changed little during the past decade. The number of RBC units transfused is an independent predictor of worse clinical outcome.

Weaning from mechanical ventilation

Weaning covers the entire process of liberating the patient from mechanical support and from the endotracheal tube. Many controversial questions remain concerning the best methods for conducting this process. An International Consensus Conference was held in April 2005 to provide recommendations regarding the management of this process. An 11-member international jury answered five pre-defined questions. 1) What is known about the epidemiology of weaning problems? 2) What is the pathophysiology of weaning failure? 3) What is the usual process of initial weaning from the ventilator? 4) Is there a role for different ventilator modes in more difficult weaning? 5) How should patients with prolonged weaning failure be managed? The main recommendations were as follows. 1) Patients should be categorised into three groups based on the difficulty and duration of the weaning process. 2) Weaning should be considered as early as possible. 3) A spontaneous breathing trial is the major diagnostic test to determine whether patients can be successfully extubated. 4) The initial trial should last 30 min and consist of either T-tube breathing or low levels of pressure support. 5) Pressure support or assist–control ventilation modes should be favoured in patients failing an initial trial/trials. 6) Noninvasive ventilation techniques should be considered in selected patients to shorten the duration of intubation but should not be routinely used as a tool for extubation failure.

Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double-blind, placebo-controlled trial.

ObjectiveTo determine whether the administration of recombinant human erythropoietin (rHuEPO) to critically ill patients in the intensive care unit (ICU) would reduce the number of red blood cell (RBC) transfusions required. DesignA prospective, randomized, double-blind, placebo- controlled, multicenter trial. SettingICUs at three academic tertiary care medical centers. PatientsA total of 160 patients who were admitted to the ICU and met the eligibility criteria were enrolled in the study (80 into the rHuEPO group; 80 into the placebo group). InterventionsPatients were randomized to receive either rHuEPO or placebo. The study drug (300 units/kg of rHuEPO or placebo) was administered by subcutaneous injection beginning ICU day 3 and continuing daily for a total of 5 days (until ICU day 7). The subsequent dosing schedule was every other day to achieve a hematocrit (Hct) concentration of >38%. The study drug was given for a minimum of 2 wks or until ICU discharge (for subjects with ICU lengths of stay >2 wks) up to a total of 6 wks (42 days) postrandomization. Measurements and Main ResultsThe cumulative number of units of RBCs transfused was significantly less in the rHuEPO group than in the placebo group (p < .002, Kolmogorov-Smirnov test). The rHuEPO group was transfused with a total of 166 units of RBCs vs. 305 units of RBCs transfused in the placebo group. The final Hct concentration of the rHuEPO patients was significantly greater than the final Hct concentration of placebo patients (35.1 ± 5.6 vs. 31.6 ± 4.1;p < .01, respectively). A total of 45% of patients in the rHuEPO group received a blood transfusion between days 8 and 42 or died before study day 42 compared with 55% of patients in the placebo group (relative risk, 0.8; 95% confidence interval, 0.6, 1.1). There were no significant differences between the two groups either in mortality or in the frequency of adverse events. ConclusionsThe administration of rHuEPO to critically ill patients is effective in raising their Hct concentrations and in reducing the total number of units of RBCs they require. (Crit Care Med 1999; 27:2346–2350)

Simvastatin Rescues Rats From Fatal Pulmonary Hypertension by Inducing Apoptosis of Neointimal Smooth Muscle Cells

Background—Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. Methods and Results—Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg · kg−1 · d−1 by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-&agr; and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. Conclusions—Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.

Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation.

The latent plasma carboxypeptidase thrombin-activable fibrinolysis inhibitor (TAFI) is activated by thrombin/thrombomodulin on the endothelial cell surface, and functions in dampening fibrinolysis. In this study, we examined the effect of activated TAFI (TAFIa) in modulating the proinflammatory functions of bradykinin, complement C5a, and thrombin-cleaved osteopontin. Hydrolysis of bradykinin and C5a and thrombin-cleaved osteopontin peptides by TAFIa was as efficient as that of plasmin-cleaved fibrin peptides, indicating that these are also good substrates for TAFIa. Plasma carboxypeptidase N, generally regarded as the physiological regulator of kinins, was much less efficient than TAFIa. TAFIa abrogated C5a-induced neutrophil activation in vitro. Jurkat cell adhesion to osteopontin was markedly enhanced by thrombin cleavage of osteopontin. This was abolished by TAFIa treatment due to the removal of the C-terminal Arg168 by TAFIa from the exposed SVVYGLR α4β1 integrin-binding site in thrombin-cleaved osteopontin. Thus, thrombin cleavage of osteopontin followed by TAFIa treatment may sequentially up- and down-modulate the pro-inflammatory properties of osteopontin. An engineered anticoagulant thrombin, E229K, was able to activate endogenous plasma TAFI in mice, and E229K thrombin infusion effectively blocked bradykinin-induced hypotension in wild-type, but not in TAFI-deficient, mice in vivo. Our data suggest that TAFIa may have a broad anti-inflammatory role, and its function is not restricted to fibrinolysis.

Biguanide-Associated Lactic Acidosis: Case Report and Review of the Literature

PURPOSE The biguanides are a class of oral hypoglycemic agents that are commonly used in the treatment of diabetes mellitus. Such agents include metformin, phenformin, and buformin. The use of phenformin was discontinued in the United States in 1976 because of probable association with lactic acidosis. However, metformin is currently in common use in many parts of the world. In this report, we describe a patient with severe lactic acidosis secondary to metformin administration, and review the literature relevant to biguanide-associated lactic acidosis. PATIENT We describe a diabetic man with end-stage renal failure and diabetes mellitus who was hospitalized with life-threatening lactic acidosis (lactate, 10.9 mmol/L). Unbeknownst to the hospital staff, he was being treated with metformin, which had been prescribed in Indonesia. RESULTS Arterial blood gas analysis revealed a pH of 6.76 and a bicarbonate level of 1.6 mmol/L prior to treatment. Following therapy, which included oxygen, volume expansion, other supportive therapy, and hemodialysis, the patient completely recovered and was discharged from the hospital. CONCLUSIONS Lactic acidosis can complicate biguanide therapy in diabetic patients with renal insufficiency. We review the literature relevant to the pathogenesis and therapy of biguanide-associated lactic acidosis. Physicians who have completed their training after 1976 may not be familiar with metformin and other biguanides, but with the increasing numbers of immigrants to the United States, physicians should be aware of the potential complications of these medications.

Hyperglycemia decreases acute neuronal ischemic changes after middle cerebral artery occlusion in cats.

Hyperglycemia has been reported to worsen the tolerance of the brain to ischemia, and it has therefore been recommended that patients undergoing neurosurgical procedures not receive glucose-containing solutions. However, whereas most animal studies have used global ischemia models, most neurosurgical procedures are associated with risks of focal rather than global ischemia. We therefore studied the effects of glucose administration in an animal model of focal cerebral ischemia. We anesthetized 20 cats with halothane (0.85% end tidal in oxygen), and a focal cerebral ischemic lesion was produced by clip ligation of the left middle cerebral artery using a transorbital approach. Hyperglycemia (10 cats, mean +/- SEM plasma glucose concentration 561 +/- 36 mg/dl) was established before ligation by infusion of 50% glucose in 0.45% saline; the control group (10 cats, mean +/- SEM plasma glucose concentration 209 +/- 28 mg/dl) received 0.45% saline only. Total fluid administered, mean arterial blood pressure, body temperature, and arterial blood gas values did not differ between the two groups 0, 2, and 6 hours after ligation. The cats were killed 6 hours after ligation, and the area of severe ischemic neuronal damage was determined by microscopic examination of a coronal section at the level of the optic chiasm. The mean +/- SEM area of left cortical severe ischemic neuronal damage was 12 +/- 2% of the left cortex in the hyperglycemic group compared with 28 +/- 5% in the control group (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis.

Sepsis is a complex, incompletely understood and often fatal disorder, typically accompanied by hypotension, that is considered to represent a dysregulated host response to infection. Neurotensin (NT) is a 13-amino-acid peptide that, among its multiple effects, induces hypotension. We find that intraperitoneal and plasma concentrations of NT are increased in mice after severe cecal ligation and puncture (CLP), a model of sepsis, and that mice treated with a pharmacological antagonist of NT, or NT-deficient mice, show reduced mortality during severe CLP. In mice, mast cells can degrade NT and reduce NT-induced hypotension and CLP-associated mortality, and optimal expression of these effects requires mast cell expression of neurotensin receptor 1 and neurolysin. These findings show that NT contributes to sepsis-related mortality in mice during severe CLP and that mast cells can lower NT concentrations, and suggest that mast cell–dependent reduction in NT levels contributes to the ability of mast cells to enhance survival after CLP.

Adoption of anesthesia information management systems by academic departments in the United States.

BACKGROUND: Information technology has been promoted as a way to improve patient care and outcomes. Whereas information technology systems for ancillary hospital services (e.g., radiology, pharmacy) are deployed commonly, it has been estimated that anesthesia information management systems (AIMS) are only installed in a small fraction of United States (US) operating rooms. In this study, we assessed the adoption of AIMS at academic anesthesia departments and explored the motivations for and resistance to AIMS adoption. METHODS: Members of the Society of Academic Anesthesiology Chairs and the Association of Anesthesiology Program Directors were solicited by e-mail to participate in an online survey of AIMS adoption. Two months after closing the survey, another e-mail was sent with a single question asking for an update to their AIMS implementation status. RESULTS: Surveys were fully completed by 48 (34%) of the 140 Society of Academic Anesthesiology Chairs and Association of Anesthesiology Program Directors departments surveyed, with 72 (51%) providing AIMS status information. Twenty of these 72 departments have an AIMS installed, 12 are currently implementing, 11 have selected but not yet installed, and 18 are planning to purchase an AIMS in 2008 or 2009. Therefore, at least 61 (44%) of all 140 US academic anesthesia departments have committed to AIMS. This estimated adoption rate is conservative because the numerator equals the affirmative responses, whereas the denominator equals the total population of academic departments. Among adopters, the top ranked anticipated benefits from installing an AIMS included improved clinical documentation, improved data collection for clinical research, enhancement of quality improvement programs, and compliance with requirements of regulatory authorities. The hospital provided funding in almost all facilities (90%), with co-funding by the anesthesia group in 35%. CONCLUSIONS: At least 61 or 44% of the 140 US academic departments surveyed in this study have already implemented, are planning to acquire, or are currently searching for an AIMS. Adoption of AIMS technology appears to have reached sufficient momentum within academic anesthesiology departments to result in a fundamental change.

Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia.

In clinical medicine, cerebral ischemia is frequently due to a focal, rather than global, insult. The effect of hyperglycemia in focal cerebral ischemia is not well defined. We studied the effect of hyperglycemia on neuropathologic changes in a rabbit model of focal cerebral ischemia. Rabbits were randomized to receive saline (n = 12) or glucose (n = 12) infusions. The left anterior cerebral and left internal carotid arteries were clipped after the infusion began. After 6 hours of occlusion, the area of severe ischemic neuronal damage in the left neocortex and striatum on two standard sections of brain was calculated and expressed as a percentage of the total area of the left cortex or striatum. The mean +/- SEM cortical area of severe ischemic neuronal damage was 22.1 +/- 2.8% in the glucose-treated rabbits and 34.0 +/- 4.6% in the saline-treated rabbits (p less than 0.05). The cortical area of severe ischemic neuronal damage was inversely correlated with plasma glucose concentration at the time of arterial clipping (p less than 0.05). We conclude that hyperglycemia is associated with decreased histologic neuronal injury in this model of focal cerebral ischemia and may be protective when cerebral ischemia occurs from a focal insult.