Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness.

PURPOSE: The purpose of this article was to determine the prevalence of iron, vitamin B12, and folate deficiency and to evaluate the erythropoietin (EPO) response to anemia in a cohort of long-term intensive care unit (ICU) patients. MATERIALS AND METHODS: All patients admitted to three academic medical center multidisciplinary ICUs were screened for eligibility into a randomized trial of EPO for the treatment of ICU anemia. On their second or third ICU day, patients enrolled in this trial had EPO levels drawn and were screened for iron, B12, and folate deficiency. Weekly EPO levels were obtained throughout patients' ICU stay. RESULTS: A total of 184 patients were screened for iron, B12, and folate deficiency. Sixteen patients (9%) were iron deficient by study criteria, 4 (2%) were B12 deficient, and 4 (2%) were folate deficient. Mean hemoglobin and reticulocyte percents of the remaining 160 patients were 10.3 +/- 1.2 g/dL and 1.66 +/- 1.09%, respectively. In most patients, serum iron and total iron binding capacity levels were very low, whereas ferritin levels were very high. Mean and median day 2 EPO levels were 35.2 +/- 35.6 mIU/mL and 22.7 mIU/mL, respectively (normal = 4.2-27.8). Serial EPO levels in most persistently anemic patients remained within the normal range. CONCLUSIONS: In this cohort, screening for iron, B12, and folate deficiency identified potentially correctable abnormalities in more than 13% of patients and should be considered in those who are anticipated to have long ICU stays. Even at an early point of critical illness, most patients had iron studies consistent with anemia of chronic disease (ACD), as well as a blunted EPO response that may contribute to this ACD-like anemia of critical illness.

40-O-(2-hydroxyethyl)-rapamycin attenuates pulmonary arterial hypertension and neointimal formation in rats.

Pneumonectomized rats develop pulmonary hypertension (PH) and pulmonary vascular neointimal formation 4 wk after monocrotaline (MCT) administration. Male Sprague-Dawley rats were injected with MCT (60 mg/kg) on Day 7 after left pneumonectomy. Three groups (n = 5) received 40-O-(2-hydroxyethyl)-rapamycin (RAD, 2.5 mg/kg/d, by gavage): Group PMR(5-35) from Day 5 to Day 35, Group PMR5-14 from Day 5 to Day 14, and Group PMR15-35 from Day 15 to Day 35. By Day 35, rats that received vehicle had higher mean pulmonary arterial pressures (Ppa = 41 +/- 3 mm Hg) (p < 0.001), right ventricular systolic pressures (Prv,s = 45 +/- 2 mm Hg) (p < 0.01), and right ventricle/(left ventricle plus septum) (0.55 +/- 0.05) (p = 0.028) than rats in Groups PMR5-35 (Ppa = 25 +/- 3 mm Hg, Prv,s = 32 +/- 7 mm Hg, RV/LV&S = 0.42 +/- 0.06) and PMR5-14 (Ppa = 29 +/- 4 mm Hg, Prv,s = 30 +/- 5 mm Hg, RV/LV&S = 0.43 +/- 0.07). Pulmonary arterial neointimal formation (quantified by a vascular occlusion score) was more severe in vehicle-treated rats (1.93 +/- 0.03) than in Groups PMR5-14 (1.56 +/- 0.27) and PMR(5-35) (1.57 +/- 0.1) (p < 0.01). RAD attenuates the development of MCT-induced pulmonary arterial hypertension in the pneumonectomized rat.

Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats.

This paper reports the effect of triptolide (a diterpenoid triepoxide) on the development of monocrotaline (MCT)-induced pulmonary hypertension in pneumonectomized rats. Male Sprague- Dawley rats were injected with MCT (60 mg/kg) on Day 7 after left pneumonectomy. Rats received therapy from Day 5 to 35 with triptolide (0.25 mg/kg intraperitoneally, every other day, n = 10), or vehicle (0.1 ml of ethanol/cremophor intraperitoneally, every other day, n = 10). By Day 35, triptolide-treated rats demonstrated lower mean pulmonary arterial pressure (mPAP) than vehicle-treated rats (mPAP 21 +/- 3 versus 42 +/- 5 mm Hg, p < 0.001). Triptolide-treated rats also had significantly less right ventricular hypertrophy (RVH) and pulmonary arterial neointimal formation. In a rescue experiment, rats initiated therapy on Day 21. At Day 35, vehicle-treated rats (n = 4) had higher mPAP (40 +/- 9 mm Hg), greater RVH, and more severe pulmonary arterial neointimal formation than rats that received triptolide (0.25 mg/kg every other day, n = 7, mPAP 30 +/- 4 mm Hg) and rats that received triptolide (0.2 mg/kg daily, n = 7, mPAP 25 +/- 5 mm Hg, p < 0.01). In pneumonectomized rats that receive MCT, triptolide attenuates the development of pulmonary hypertension and RVH, and promotes regression of pulmonary arterial neointimal formation.

Combined therapy with zaprinast and inhaled nitric oxide abolishes hypoxic pulmonary hypertension.

OBJECTIVE: To determine whether the combination of the phosphodiesterase 5 inhibitor zaprinast and inhaled nitric oxide (NO) decreases hypoxic pulmonary hypertension in the rat. DESIGN: Prospective, experimental study. SETTING: Animal laboratory of a university medical center. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Anesthetized rats were mechanically ventilated and instrumented for measurement of mean systemic arterial pressure, pulmonary arterial pressure, and cardiac output. In group 1, four acute hypoxic challenges (FIO2 = 0.17 for 5 mins) were performed: initial, during 40 ppm inhaled NO, immediately after discontinuation of 5 mins of inhaled NO, and final. In group 2 rats, an initial hypoxic challenge was performed and rats then received zaprinast (3 mg/kg bolus followed by 0.3 mg/kg/min infusion). Four hypoxic challenges analogous to group 1 were then performed during zaprinast administration. MEASUREMENTS AND MAIN RESULTS: Initial hypoxic challenge produced similar increases in pulmonary arterial pressure in both groups. In group 1, inhaled NO either only before or only during hypoxia decreased the pulmonary hypertensive response to hypoxia. In group 2, zaprinast administration did not alter hemodynamics. Zaprinast alone decreased the pulmonary hypertensive response to hypoxia. The combination of zaprinast and inhaled NO (either before or during hypoxia) abolished the pulmonary hypertensive response to hypoxia. CONCLUSIONS: Treatment with inhaled NO for 5 mins before but not during hypoxia is as effective as inhaled NO during hypoxia. Inhaled NO and zaprinast both decrease the pulmonary hypertensive response to hypoxia, and the combination abolishes the response. The combination of a phosphodiesterase 5 inhibitor and inhaled NO may have clinical applicability in the treatment of pulmonary hypertension.

Combination therapy with inhaled nitric oxide and intravenous dobutamine during pulmonary hypertension in the rabbit.

Combination therapy with an intravenous inovasodilator and inhaled nitric oxide (NO) may be appropriate in patients with pulmonary hypertension and associated right ventricular failure. We examined whether dobutamine and inhaled NO would have additive pulmonary vasodilator effects in experimental pulmonary hypertension. Pulmonary hypertension was produced in anesthetized, mechanically ventilated rabbits by infusion of U46619, a thromboxane analogue. Dobutamine was administered in increasing doses (2.5-20 microg/kg/min) with and without inhaled NO (40 ppm). Dobutamine produced dose-dependent decreases in pulmonary vascular resistance (PVR) and mean arterial pressure (MAP) and increases in cardiac output (CO). Inhaled NO alone decreased pulmonary artery pressure (PAP) and PVR with no effect on MAP or CO. The effects of dobutamine and inhaled NO were additive, so that at each dose of dobutamine, inhaled NO decreased PAP and PVR with no effect on systemic hemodynamics. This study suggests that the combination of dobutamine and inhaled NO should produce additive pulmonary vasodilation in patients with pulmonary hypertension and associated right ventricular dysfunction.

Sonic vibrational analysis provides continuous measurement of arterial properties.

OBJECTIVE: We describe a new technology for measuring artery mechanical properties, called Sonic Vibrational Analysis (SVA). We utilize SVA to study the changes in radial artery smooth muscle tone caused by intravenous infusion of vasoactive agents. METHODS: Six healthy volunteers were monitored with a radial intra-arterial catheter and an SVA sensor during progressively increasing doses of nitroglycerin (NTG), phenylephrine, sodium nitroprusside (SNP), dobutamine, and nicardipine. In SVA, the propagation velocity of an audio-frequency vibration is measured over a short segment of the radial artery. The measurement has sufficient temporal resolution to track the continuous changes in arterial properties that occur due to the natural blood pressure pulse. RESULTS: Coupled with the measurement of radial blood pressure, SVA allowed determination of the physiological/mechanical state of the artery within a single cardiac cycle. NTG, SNP, and phenylephrine caused significant changes in both blood pressure and the physiological state of the radial artery. Nicardipine and dobutamine altered blood pressure without change in the state of the radial artery. CONCLUSIONS: The current results are consistent with previous studies of the effects of vasoactive agents on the radial artery. SVA is non-invasive, continuous, localized to a well-defined section of artery, and suitable for the collection of large volumes of time-resolved data in a laboratory or clinical setting.

Inhaled nitric oxide and pulmonary vasoreactivity.

Inhaled nitric oxide is a ubiquitous molecule which is produced endogenously and is also found in air pollution and in cigarette smoke. After describing the chemistry of NO, we review its history from the first description in 1980 to the current clinical indications. The biosynthesis of NO, its effects on pulmonary vasoreactivity, and the administration of inhaled NO will be described. The indications, uses, and side effects of inhaled NO are discussed with an emphasis on withdrawal of NO therapy, specifically the "rebound" phenomenon. Possible drug interactions are listed. Inhaled nitric oxide is here to stay, and future studies will provide more information on its therapeutic dose, duration and potential toxicity.

Additive effects of inhaled nitric oxide and intravenous milrinone in experimental pulmonary hypertension.

OBJECTIVE: To determine whether inhaled nitric oxide (IN0) and intravenous milrinone have additive pulmonary vasodilator effects in a rat model of pulmonary hypertension. DESIGN: Prospective, experimental study. SETTING: Animal laboratory of a university medical center. SUBJECTS: Male New Zealand White rabbits. INTERVENTIONS: Anesthetized rabbits were mechanically ventilated and instrumented for measurement of systemic mean arterial pressure (MAP), pulmonary artery pressure (PAP), left atrial pressure, and cardiac output (CO). After baseline measurements, the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (30 mg/kg iv) was administered. Pulmonary hypertension was produced by the continuous infusion of U46619, a thromboxane A2 mimetic. INO (40 ppm) was added to the inspired gas, and hemodynamic measurements were obtained before and after INO. Milrinone was administered sequentially as a 30-mg/kg bolus followed by a 3-microg/kg/min infusion, a 100-mg/kg bolus followed by a 10-microg/kg/min infusion, and a 300-mg/kg bolus followed by a 30-microg/kg/min infusion (M3). Hemodynamic measurements were obtained with and without INO at each dose of milrinone. MEASUREMENTS AND MAIN RESULTS: During U46619-induced pulmonary hypertension, INO decreased PAP and pulmonary vascular resistance (PVR) but did not affect MAP, systemic vascular resistance (SVR), or CO. Milrinone dose dependently decreased PAP, PVR, MAP, and SVR and increased CO. At each dose of milrinone, INO further decreased PVR but not SVR. M3 decreased PVR 49%, and the addition of INO decreased PVR an additional 19% so that PAP and PVR decreased to baseline values. CONCLUSIONS: Milrinone and INO both decrease pulmonary hypertension individually, and the combination produces additive effects. Combination therapy may produce potent and selective pulmonary vasodilation during the treatment of pulmonary hypertension.

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

OBJECTIVE: To 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. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter trial. SETTING: ICUs at three academic tertiary care medical centers. PATIENTS: A 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). INTERVENTIONS: Patients 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 RESULTS: The 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. CONCLUSIONS: The 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.

Combined therapy with inhaled nitric oxide and intravenous vasodilators during acute and chronic experimental pulmonary hypertension.

UNLABELLED: Both inhaled nitric oxide (NO) and IV vasodilators decrease pulmonary hypertension, but the effects of combination therapy are unknown. We studied the response to inhaled NO (100 ppm) alone, IV vasodilator alone, and combined therapy during acute (U46619-induced) and chronic (monocrotaline-induced) pulmonary hypertension in the pentobarbital-anesthetized rat. Vasodilator doses were 1.0, 3.2, 10, and 32 microg x kg(-1) x min(-1) sodium nitroprusside (SNP); 50, 100, 150, 200, and 300 microg x kg(-1) x min(-1) adenosine; or 25, 50, 150, 200, and 300 ng x kg(-1) x min(-1) prostacyclin. In the absence of IV vasodilator therapy, inhaled NO decreased mean pulmonary artery pressure without decreasing mean systemic arterial pressure. In both acute and chronic pulmonary hypertension, the addition of inhaled NO to the largest dose of adenosine or prostacyclin, but not of SNP, decreased pulmonary artery pressure. Because inhaled NO and SNP activate guanylyl cyclase and adenosine and prostacyclin activate adenylyl cyclase, the results suggest that adding inhaled NO to a vasodilator not dependent on guanylyl cyclase may produce additional selective pulmonary vasodilation. IMPLICATIONS: In therapy of pulmonary hypertension, inhaled nitric oxide should produce additional selective pulmonary vasodilation when combined with a vasodilator whose mechanism of action is not dependent on cyclic guanosine 3',5'-monophosphate.

Combined inhaled nitric oxide and inhaled prostacyclin during experimental chronic pulmonary hypertension.

Inhaled nitric oxide (NO) and inhaled prostacyclin (PGI2) produce selective reductions in pulmonary vascular resistance (PVR) through differing mechanisms. NO decreases PVR via cGMP, and PGI2 produces pulmonary vasodilation via cAMP. As a general pharmacological principle, two drugs that produce similar effects via different mechanisms should have additive or synergistic effects when combined. We designed this study to investigate whether combined inhaled NO and PGI2 therapy results in additive effects during chronic pulmonary hypertension in the rat. Monocrotaline injected 4 wk before study produced pulmonary hypertension in all animals. Inhaled NO (20 parts/million) reversibly and selectively decreased pulmonary artery pressure (Ppa) with a mean reduction of 18%. Four concentrations of PGI2 were administered via inhalation (5, 10, 20, and 80 microg/ml), both alone and combined with inhaled NO. Inhaled PGI2 alone decreased Ppa in a dose-dependent manner with no change in mean systemic arterial pressure. Combined inhaled NO and PGI2 selectively and significantly decreased Ppa more did than either drug alone. The effects were additive at the lower concentrations of PGI2 (5, 10, and 20 microg/ml). The combination of inhaled NO and inhaled PGI2 may be useful in the management of pulmonary hypertension.

Inhaled nitric oxide potentiates actions of adenosine but not of sodium nitroprusside in experimental pulmonary hypertension.

Inhaled nitric oxide (NO), a selective pulmonary vasodilator, increases intracellular cyclic guanosine monophosphate. In contrast, adenosine, another selective pulmonary vasodilator, increases intracellular cyclic adenosine monophosphate. There has been only limited study on effects of inhaled NO combined with other pulmonary vasodilators. The current study examined the hypothesis that inhaled NO would potentiate in vivo pulmonary vasodilator effects of adenosine, but not those of sodium nitroprusside (SNP). Like inhaled NO, SNP acts via cyclic guanosine monophosphate. Rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor NG-nitro-L-arginine methyl ester was administered. U46619, a thromboxane A2 mimetic, was infused to produce pulmonary hypertension. Rabbits then received either SNP at doses of 0.5, 1, 2, 4, 8, 16, and 32 microg/kg/min or adenosine at doses of 12.5, 25, 50, 100, 150, and 300 microg/kg/min. Hemodynamic measurements were obtained with or without inhaled NO (40 ppm) at each dose of SNP or adenosine. During U46619-induced pulmonary hypertension, inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance. Adenosine and SNP produced dose-related decreases in pulmonary artery pressure and pulmonary vascular resistance and increases in cardiac output. Inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance at all doses of adenosine, but had no significant pulmonary vasodilator effects at doses of SNP >0.5 microg/kg/min. We conclude that inhaled NO does not produce additional pulmonary vasodilation over that achieved at higher doses of SNP, but does produce additional vasodilation when combined with a vasodilator having different mechanisms of action. Since both inhaled NO and adenosine produce selective pulmonary vasodilation, such combination therapy may be effective in patients with pulmonary hypertension.

Inhibition of endogenous nitric oxide synthesis potentiates the effects of sodium nitroprusside but not of adenosine in experimental pulmonary hypertension.

This study examined the systemic and pulmonary vasodilator effects of sodium nitroprusside (SNP) and adenosine during experimental pulmonary hypertension with and without inhibition of endogenous NO synthesis. Male New Zealand White rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was administered to 15 of the 28 rabbits. Pulmonary hypertension was then produced in all rabbits by U46619, a thromboxane A2 mimetic. SNP was infused in 14 rabbits (7 L-NAME, 7 control) at doses of 0.5-20 microg/kg/min; adenosine was infused in the other 14 rabbits (8 L- NAME, 6 control) at doses of 12.5-300 microg/kg/min. The U46619 dose required to produce pulmonary hypertension was significantly lower in the L-NAME group. SNP dose-dependently decreased pulmonary (Ppa) and systemic (Psa) artery pressures and systemic vascular resistance (SVR). Both Ppa and Psa were decreased more with SNP in the L-NAME than in the no L-NAME group. The SNP ED50 for the decrease in PVR was almost threefold lower in the L-NAME group. Adenosine dose-dependently decreased Ppa, Psa, PVR and SVR. The adenosine ED50 for the decreases in PVR and SVR were similar in the L-NAME group and the control group. We conclude that inhibition of endogenous NO synthesis shifts the dose-response curves for both the pulmonary and systemic vasodilator effects to the left for the nitrovasodilator SNP but not for the non-nitrovasodilator adenosine.

Prediction of poor outcome of intensive care unit patients admitted from the emergency department.

OBJECTIVE: To assess whether physicians can identify very low likelihood of survival and very low likelihood of favorable functional outcome in adult nontrauma patients before admission to the intensive care unit (ICU) from the emergency department (ED). DESIGN: Prospective survey. SETTING: University hospital ED and ICU. PARTICIPANTS AND PATIENTS: Critical care fellows and ED physicians and all adult nontrauma patients admitted to the ICU from the ED over 1 yr. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The survey compared predictions of poor outcome from three sources: critical care fellows, ED physicians, and the admission Mortality Probability Model (MPM0). All patients were followed until hospital death or hospital discharge. Six-month follow-up data were obtained for patients predicted to have a < 2% chance of surviving with favorable functional outcome. In the ED, critical care fellows and ED physicians predicted likelihood of patient survival and likelihood of favorable functional outcome. MPM0 estimates of mortality were determined. The sensitivities, specificities, and positive predictive values were calculated for the predictions of < 2% survival and the predictions of < 2% chance of favorable functional outcome made by each prediction group. Complete data were obtained on 236 (96%) of 243 eligible patients. With regard to hospital mortality rate, fellows' predictions had a sensitivity of 27%, a specificity of 99%, and a positive predictive value of 88%; ED physicians' predictions had a sensitivity of 24%, a specificity of 98%, and a positive predictive value of 81%; and MPM0 predictions had a sensitivity of 2%, a specificity of 100%, and a positive predictive value of 100%. With regard to mortality rate combined with poor functional outcome, fellows' predictions had a sensitivity of 35%, a specificity of 99%, and a positive predictive value of 96%; ED physicians' predictions had a sensitivity of 37%, a specificity of 99%, and a positive predictive value of 96%. CONCLUSIONS: If a cutoff point of < 2% predicted survival is used in the triage of patients away from the ICU, the MPM0 has too low a sensitivity to be used as an effective screen. The low sensitivities and relatively low positive predictive values with wide confidence intervals of physician predictions of < 2% survival also preclude their use in triage. The addition of functional outcome as an end point improves the sensitivity, specificity, and positive predictive value of subjective predictions, making triage of patients away from the ICU at the time of ED evaluation a realistic possibility.

Nitroglycerin does not alter pulmonary vascular permeability in isolated rabbit lungs.

Nitroglycerin (NTG) produces vasodilation by releasing nitric oxide (NO) at the cellular level. Other studies have suggested that NO may directly alter vascular permeability and may alter the development of tissue injury. We therefore examined the effects of NTG on vascular permeability in the buffer-perfused rabbit lung under normal conditions and during lung injury. Vascular permeability was assessed by measurement of the capillary filtration coefficient (Kf,c). In normal lungs, NTG did not alter Kf,c or the rate of weight gain. Oxidant lung injury was produced by the addition of purine and xanthine oxidase and resulted in increased Kf,c and increased weight gain. However, NTG did not alter these effects of oxidant lung injury. We conclude that NTG does not alter pulmonary vascular permeability in either normal or oxidant-injured lungs.