Decisions about enteral tube feeding among the elderly

OBJECTIVE: To characterize the acute actions and physiologic dose profile of epinephrine, as a single inotrope, in patients with septic shock. DESIGN: Prospective clinical study. The relationship between epinephrine dose and cardiovascular variables was analyzed using repeated-measures analysis of variance. SETTING: ICU in a university teaching hospital. PATIENTS: Eighteen patients with septic shock, mean age 64 +/- 8 (SD) yrs, and with a mean admission Acute Physiology and Chronic Health Evaluation (APACHE II) score of 23 (range 14 to 35). INTERVENTIONS: Initial volume loading and the measurement of a baseline hemodynamic profile were followed by the administration of an epinephrine infusion at 3 microgram/min with subsequent increments of 3 micrograms/min and the determination of a hemodynamic profile after each dose increment. Therapy was titrated to clinical goals of perfusion and restoration of premorbid systolic arterial BP. MEASUREMENTS AND MAIN RESULTS: After volume loading, mean hemodynamic indices were as follows: mean arterial pressure (MAP) 62 +/- 7 mm Hg; cardiac index 3.8 +/- 1.1 L/min/m2; left ventricular stroke work index 25 +/- 11 g.m/m2; oxygen delivery (Do2) index 460 +/- 168 mL/min/m2; and oxygen consumption (VO2) index 165 +/- 64 mL/min/m2. In the dose range of 3 to 18 microgram/min, epinephrine produced linear increases in average heart rate, MAP, cardiac index, left ventricular stroke work index, stroke volume index, VO2, and DO2. No effect was noted on pulmonary artery occlusion pressure (PAOP), mean pulmonary arterial pressure, or systemic vascular resistance index. CONCLUSIONS: Epinephrine increases DO2 in septic shock by increasing cardiac index without an effect on systemic vascular resistance index or PAOP.     

Increased circulating thrombomodulin in children with septic shock

OBJECTIVES: To test the hypothesis that children diagnosed with septic shock have increased plasma thrombomodulin values as a manifestation of microcirculatory dysfunction and endothelial injury; to determine whether plasma thrombomodulin concentrations are associated with the extent of multiple organ system failure and mortality. DESIGN: Prospective, cohort study. SETTING: Pediatric intensive care unit. PATIENTS: Twenty-two children with septic shock and ten, healthy, control children. INTERVENTIONS: Blood samples were obtained for plasma thrombomodulin determinations every 6 hrs for 72 hrs in septic shock patients and once in healthy control patients. MEASUREMENTS AND MAIN RESULTS: Thirty-two children (22 septic shock, and 10 healthy controls) were enrolled in the study. Thrombomodulin concentrations were determined by an enzyme-linked immunosorbent assay. Septic shock nonsurvivors had significantly greater mean thrombomodulin concentrations (10.6 +/- 2.2 ng/mL) than septic shock survivors (5.5 +/- 0.6 ng/mL) (p < .05) and healthy control patients (3.4 +/- 0.2 ng/mL) (p < .01). Mean thrombomodulin values increased as the number of organ system failures increased. CONCLUSIONS: Pediatric survivors and nonsurvivors of septic shock have circulating thrombomodulin concentrations 1.5 and 3 times greater than healthy control patients. These findings likely represent sepsis-induced endothelial injury. Patients with multiple organ system failure have circulating thrombomodulin concentrations which are associated with the extent of organ dysfunction. We speculate that measurement of plasma thrombomodulin concentrations in septic shock may be a useful indicator of the severity of endothelial damage and the development of multiple organ system failure.     

Progressive intermittent claudication is associated with impaired fibrinolysis

OBJECTIVES: Preliminary studies have suggested that low doses of corticosteroids might rapidly improve hemodynamics in late septic shock treated with catecholamines. We examined the effect of hydrocortisone on shock reversal, hemodynamics, and survival in this particular setting. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Two intensive care units of a University hospital. PATIENTS: Forty-one patients with septic shock requiring catecholamine for >48 hrs. INTERVENTIONS: Patients were randomly assigned either hydrocortisone (100 mg i.v. three times daily for 5 days) or matching placebo. MEASUREMENTS AND MAIN RESULTS: Reversal of shock was defined by a stable systolic arterial pressure (>90 mm Hg) for > or =24 hrs without catecholamine or fluid infusion. Of the 22 hydrocortisone-treated patients and 19 placebo-treated patients, 15 (68%) and 4 (21%) achieved 7-day shock reversal, respectively, a difference of 47% (95% confidence interval 17% to 77%; p = .007). Serial invasive hemodynamic measurements for 5 days did not show significant differences between both groups. At 28-day follow-up, reversal of shock was higher in the hydrocortisone group (p = .005). Crude 28-day mortality was 7 (32%) of 22 treated patients and 12 (63%) of 19 placebo patients, a difference of 31% (95% confidence interval 1% to 61%; p = .091). Shock reversal within 7 days after the onset of corticosteroid therapy was a very strong predictor of survival. There were no significant differences in outcome in responders and nonresponders to a short corticotropin test. The respective rates of gastrointestinal bleeding and secondary infections did not differ between both groups. CONCLUSIONS: Administration of modest doses of hydrocortisone in the setting of pressor-dependent septic shock for a mean of >96 hrs resulted in a significant improvement in hemodynamics and a beneficial effect on survival. These beneficial effects do not appear related to adrenocortical insufficiency.     

Value of single oral loading dose of propafenone in converting recent-onset atrial fibrillation. Results of a randomized, double-blind, controlled study

OBJECTIVE: To assess the effects of dobutamine at a rate of 5 micrograms/kg/min on hemodynamics and gastric intramucosal acidosis in patients with hyperdynamic septic shock treated with epinephrine. DESIGN: A prospective, interventional, clinical trial. SETTING: An adult, 16-bed medical/surgical intensive care unit of a university hospital. PATIENTS: Twenty septic shock patients with a mean arterial pressure of > 75 mm Hg and a cardiac index of > 3.5 L/min/m2. INTERVENTIONS: After baseline measurements (H0), each patient received dobutamine at a rate of 5 micrograms/kg/min. Baseline measurements included: hemodynamic parameters, tonometric parameters, arterial and mixed venous gases, and arterial lactate concentrations. These measurements were repeated after 1 (H1), 2 (H2), and 3 (H3) hrs. After H2 measurements, dobutamine was stopped. The patients were separated into two groups according to their PCO2 gap (tonometer PCO2-PaCO2). The increased PCO2 gap group was defined by a PCO2 gap > 8 torr (> 1.1 kPa) (n = 13), and the normal PCO2 gap group by a PCO2 gap < or = 8 torr (< or = 1.1 kPa)(n = 7). MEASUREMENTS AND MAIN RESULTS: Dobutamine at 5 micrograms/kg/min had no significant effects on mean arterial pressure, heart rate, cardiac index, systemic vascular resistance, oxygen delivery, and oxygen consumption in epinephrine-treated septic shock. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. During dobutamine infusion, arterial lactate concentration decreased from 5.1 +/- 0.4 in the increased PCO2 gap group and 4.2 +/- 0.4 in the normal PCO2 gap group to 3.9 +/- 0.3 and 3.5 +/- 0.3 mmol/L, respectively (p < .01). The PCO2 gap decreased and gastric intramucosal pH increased in the increased PCO2 gap group from 12 +/- 0.8 (1.6 +/- 0.1 kPa) to 3.5 +/- 0.8 torr (0.5 +/- 0.1 kPa) (p < .01) and from 7.11 +/- 0.03 to 7.18 +/- 0.02 (p < .01), respectively, and did not change in the normal PCO2 gap group. After stopping dobutamine infusion, the PCO2 gap and intramucosal pH returned to baseline values in the increased PCO2 gap group. CONCLUSION: The addition of 5 micrograms/kg/min of dobutamine added to epinephrine in hyperdynamic septic shock selectively improved the adequacy of gastric mucosal perfusion without modification in systemic hemodynamics.     

Does N-acetyl-L-cysteine influence cytokine response during early human septic shock?

STUDY OBJECTIVE: To assess the effects of adjunctive treatment with N-acetyl-L-cysteine (NAC) on hemodynamics, oxygen transport variables, and plasma levels of cytokines in patients with septic shock. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: A 24-bed medicosurgical ICU in a university hospital. PATIENTS: Twenty-two patients included within 4 h of diagnosis of septic shock. INTERVENTIONS: Patients were randomly allocated to receive either NAC (150 mg/kg bolus, followed by a continuous infusion of 50 mg/kg over 4 h; n= 12) or placebo (n=10) in addition to standard therapy. MEASUREMENTS: Plasma concentrations of tumor necrosis factor-alpha (TNF), interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor-alpha receptor-p55 (sTNFR-p55) were measured by sensitive immunoassays at 0, 2, 4, 6 and 24 h. Pulmonary artery catheter-derived hemodynamics, blood gases, hemoglobin, and arterial lactate were measured at baseline, after infusion (4 h), and at 24 h. RESULTS: NAC improved oxygenation (PaO2/FIO2 ratio, 214+/-97 vs 123+/-86; p<0.05) and static lung compliance (44+/-11 vs 31+/-6 L/cm H2O; p<0.05) at 24 h. NAC had no significant effects on plasma TNF, IL-6, or IL-10 levels, but acutely decreased IL-8 and sTNFR-p55 levels. The administration of NAC had no significant effect on systemic and pulmonary hemodynamics, oxygen delivery, and oxygen consumption. Mortality was similar in both groups (control, 40%; NAC, 42%) but survivors who received NAC had shorter ventilator requirement (7+/-2 days vs 20+/-7 days; p<0.05) and were discharged earlier from the ICU (13+/-2 days vs 32+/-9 days; p<0.05). CONCLUSION: In this small cohort of patients with early septic shock, short-term IV infusion of NAC was well-tolerated, improved respiratory function, and shortened ICU stay in survivors. The attenuated production of IL-8, a potential mediator of septic lung injury, may have contributed to the lung-protective effects of NAC.     

Effect of administration and subsequent cessation of buserelin on cancellous bone of female rats

OBJECTIVE: Low-dose dopamine has been used in critically ill patients to minimize renal dysfunction without sufficient data to support its use. The aim of this study was to determine whether low-dose dopamine improves renal function, and whether dobutamine, a nondopaminergic inotrope, improves renal function. DESIGN: Prospective, randomized, double-blind trial. PATIENTS: Twenty-three patients at risk for renal dysfunction were entered into the study. Five patients were later withdrawn. Study data for the remaining 18 patients were: mean age 55 yrs; mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 18; mean weight 71 kg). The following conditions were present: mechanical ventilation (n = 17 [inverse-ratio ventilation, n = 6]); inotrope administration (n = 11); sepsis (n = 13); and adult respiratory distress syndrome or multiple organ failure syndrome (n = 9). INTERVENTIONS: The study patients were administered dopamine (200 micrograms/min), dobutamine (175 micrograms/min), and placebo (5% dextrose) over 5 hrs each in a randomized order. Ventilator settings, fluid management, and preexisting inotropic support were not altered during the study. MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamic values and indices of renal function (4-hr urine volume, fractional excretion of sodium, and creatinine clearance) were measured during the last 4 hrs of each infusion. Dopamine produced a diuresis (145 +/- 148 mL/hr) compared with placebo (90 +/- 44 mL/hr; p < .01) without a change in creatinine clearance. Conversely, dobutamine caused a significant increase in creatinine clearance (97 +/- 54 mL/min) compared with placebo (79 +/- 38 mL/min; p < .01), without an increase in urine output. CONCLUSIONS: In stable critically ill patients, dopamine acted primarily as a diuretic and did not improve creatinine clearance. Dobutamine improved creatinine clearance without a significant change in urine output.     

Microvascular function and rheologic changes in hyperdynamic sepsis

OBJECTIVE: To investigate the rheologic changes and circulatory abnormalities at the microvascular level during severe sepsis. DESIGN: Prospective, controlled trial. SETTING: Medical and surgical intensive care units of a university-affiliated hospital. PATIENTS: Nine normal controls and eight adult patients with severe sepsis who met the study entrance criteria. INTERVENTIONS: Forearm blood flow was measured at rest and during reactive hyperemia by air plethysmography. Simultaneous hemodynamic measurements and blood samples for rheologic measurements were taken. MEASUREMENTS AND MAIN RESULTS: Red blood cell deformability index was determined using a simple filtration procedure. Leukocyte aggregation in whole human blood was detected by using a leukergy test. Expression of the neutrophil adhesion molecule CD11b/CD18 was measured using a monoclonal antibody and flow cytometry. All data were taken within 24 hrs of the patient meeting criteria for entrance into the study. Cardiac output, oxygen delivery, and oxygen consumption measurements were consistent with the hyperdynamic phase of severe sepsis. Forearm blood flow was significantly (p < .05) greater in septic patients (21 +/- 3 mL/min) than in controls (12 +/- 2 to 36 +/- 5 mL/min (p < .05), while in the septic patients, forearm blood flow during reactive hyperemia increased from 21 +/- 3 to 32 +/- 4 mL/min. The ratio of forearm blood flow during reactive hyperemia to forearm blood flow at rest was 3.2 +/- 0.1 in the controls and 1.6 +/- 0.1 in the septic patients (p < .01). The red blood cell deformability index in whole blood was significantly (p < .01) decreased in the septic patients compared with the control subjects (0.41 +/- 0.07 vs. 0.98 +/- 0.08 mL/min). This difference remained true when the hematocrit was adjusted to 45% (0.82 +/- 0.06 vs. 1.04 +/- 0.06 mL/min; p < .05). Increased expression of the neutrophil adhesion molecule CD11b/CD18 was observed in septic patients (349 +/- 46 logarithmic fluorescence units) as compared with control subjects (233 +/- 26 logarithmic fluorescence units; p < .05). Leukergy was also significantly (p < .05) increased in septic patients (17.7 +/- 3.8%) as compared with control subjects (8.9 +/- 1.6%). A significant correlation was observed between leukergy and the expression of the neutrophil adhesion molecule CD11b/CD18 in controls and septic patients (r2 = .62; p < .01). Leukergy was also inversely correlated with whole blood red blood cell deformability index (r2 = .28; p < .05). CONCLUSIONS: Reactive hyperemia in the forearm is significantly diminished in patients with sepsis, suggesting impaired microvascular blood flow. Rheologic changes, including impaired red blood cell deformability, increased leukocyte aggregation, and endothelial adherence, may contribute to this abnormality by compromising effective capillary cross-sectional area.     

Effectiveness of nitric oxide inhalation in septic ARDS

STUDY OBJECTIVE: To evaluate the percentage of nitric oxide (NO) responders in septic shock patients with ARDS. Additionally, to investigate long-term NO effects on cardiac performance and oxygen kinetic patterns in NO responders vs nonresponders. DESIGN: Prospective cohort study. SETTING: ICU of a university hospital. PATIENTS: Twenty-five consecutive patients with a diagnosis of septic shock and established ARDS requiring inotropic and vasopressor support. INTERVENTIONS: After diagnosis of ARDS, NO was administered at 18 or 36 ppm. Patients demonstrating a NO-induced rise of arterial oxygen tension of 20% or more and/or a fall in mean pulmonary artery pressure of 15% or more were grouped as NO responders; others were grouped as nonresponders. MEASUREMENTS AND RESULTS: Ten patients (40%) were NO responders, while 15 patients (60%) were nonresponders. Mortality was 40% in NO responders and 67% in nonresponders (NS). NO responders developed a significantly lower mean pulmonary artery pressure (28 +/- 6 vs 33 +/- 6 mm Hg; p < 0.05), lower pulmonary vascular resistance (PVR: 258 +/- 73 vs 377 +/- 163 dyne.s.cm-5.m-2; p < 0.05), and higher PaO2/FIO2 ratio (192 +/- 85 vs 144 +/- 74 mm Hg; p < 0.05) within the study period. In responders, NO-induced afterload reduction resulted in increased right ventricular ejection fraction (RVEF: 40 +/- 7 vs 35 +/- 9%; p < 0.05), significantly higher cardiac index (CI: 4.5 +/- 1.1 vs 4.0 +/- 1.2 L.min-1.m-2; p < 0.05) and oxygen delivery (DO2: 681 +/- 141 vs 599 +/- 160 mL.min-1.m-2; p < 0.05) compared with nonresponders. In NO nonresponders, RVEF was correlated with PVR, CI, DO2, mixed venous oxygen saturation (SvO2), and oxygen extraction ratio (O2ER) (r = +/- 0.60 to +/- 0.69; p < 0.05). No significant correlation between RVEF and any of these parameters was observed in responders. SvO2 (75 +/- 7 vs 69 +/- 8%; p < 0.05) and O2ER (0.24 +/- 0.06 vs 0.27 +/- 0.06; p < 0.05) were significantly different between responders and nonresponders, while no difference in oxygen consumption was observed (161 +/- 41 vs 153 +/- 43 mL.min.m-2). CONCLUSIONS: Inhaled NO is effective in only a subgroup of septic ARDS patients, with a higher, but insignificantly different percentage of survivors in the responder group. NO responders were characterized by increased RVEF accompanied by higher CI, DO2, and lower O2ER. In nonresponders, RVEF remained depressed, with a close correlation between RVEF and CO as well as DO2 and O2ER. Thus, nonresponders seem to suffer from impaired cardiac reserves and correspondingly lower oxygen transport variables.     

Effects of norepinephrine on right ventricular function in septic shock patients

OBJECTIVE: To study the effects of norepinephrine on right ventricular function in patients with hyperdynamic septic shock. DESIGN: Prospective, open study. SETTING: A 15 bed ICU in a university hospital. PATIENTS: 9 patients with hyperdynamic septic shock (SBP < 90 mmHg, Cl > or = 4 l.min-1.m-2, SVRI < or = 850 dynes.s.cm-5m-2 and oliguria). INTERVENTIONS: Plasma volume expansion was used to correct a suspected volume deficit and then, norepinephrine infusion was started and titrated to restore systemic blood pressure to the normal range (mean infusion rate: 1.1 +/- 0.2 mcg.kg-1.min-1). Norepinephrine was the only vasoactive agent used in these patients. MEASUREMENTS AND RESULTS: A modified Swan-Ganz catheter mounted with a fast response thermistor was inserted in each patient, allowing repeated measurements of RVEDVI and RVEF. At time of inclusion to the study, all but one patient had elevated MPAP (23 +/- 4 mmHg) and RVEF < or = 50%, and all patients had RVEDVI > or = 90 ml.m-2. During norepinephrine infusion, MAP increased from 51 +/- 9 to 89 +/- 10 mmHg (p < 0.0001), PVRI increased from 204 +/- 35 to 286 +/- 63 dynes.s.cm-5.m-2 (p < 0.05), and despite this increase in right ventricular afterload, no detrimental effect in RVEF (36 +/- 11 to 36 +/- 10%) or in RVEDVI (116 +/- 30 to 127 +/- 40 ml.m-2) was observed. A Frank-Starling relationship for the right ventricle was constructed by plotting an index of ventricular performance (RVSWI) against an index of ventricular preload (RVEDVI). A significant upward shift to the right of the relationship was observed during norepinephrine infusion. CONCLUSION: It was concluded that norepinephrine exerted a favourable effect on right ventricular function.     

Influence of angiotensin-converting enzyme inhibitor enalaprilat on endothelial-derived substances in the critically ill

OBJECTIVE: To assess the effects of the angiotensin-converting enzyme inhibitor enalaprilat on endothelial cells in septic patients. DESIGN: Prospective, randomized, placebo-controlled, blinded study. SETTING: Clinical investigation on a surgical intensive care unit of a university hospital. PATIENTS: Forty surgical septic patients (noncardiac/nonneurosurgical patients). INTERVENTIONS: After inclusion in the study and after baseline data were obtained, either 0.25 mg/hr (enalaprilat group, n = 20) or saline solution as placebo (control group, n = 20) was continuously given and continued throughout the following 5 days. MEASUREMENTS AND MAIN RESULTS: Extensive hemodynamic monitoring was carried out in all patients. Plasma concentrations of endothelin-1, angiotensin II, soluble thrombomodulin, and soluble adhesion molecules (endothelial leukocyte adhesion molecule-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and granule membrane protein-140) were measured from arterial blood samples. All measurements were carried out before the start of the infusion ("baseline" values) and daily during the following 5 days. All endothelial-derived substances (thrombomodulin, endothelin-1, and all soluble adhesion molecules) were similarly increased beyond normal in both group. Endothelin-1 increased only in the untreated control patients (from 6.9 +/- 0.7 to 14.3 +/- 1.4 mg/mL). Soluble thrombomodulin increased in the untreated control patients (from 58 +/- 9 to 79 +/- 14 ng/mL [p < .05]), but significantly decreased in the enalaprilat-treated patients. Soluble adhesion molecules increased in the untreated control group (endothelial leukocyte adhesion molecule from 92 +/- 14 to 192 +/- 29 ng/mL; intercellular adhesion molecule-1 from 480 +/- 110 to 850 +/- 119 ng/ mL) and returned almost to normal values in the enalaprilat patients. The survival rate did not differ significantly between the two groups. Control patients developed severe sepsis and septic shock more often than the enalaprilat-treated group. CONCLUSIONS: The complex pathogenesis of endothelial function abnormalities in sepsis may offer a large number of pharmacologic interventions. Administration of the angiotensin-converting enzyme inhibitor enalaprilat resulted in a reduced release of soluble endothelial-derived substances into the circulating blood, which may indicate an improved endothelial function. The specific actions of enalaprilat on the endothelium have to be elucidated in further studies.     

Dopexamine improves liver oxygenation during crystalloid resuscitation from experimental hemorrhagic shock

OBJECTIVE: To evaluate the effects of dopexamine administration on hemodynamic variables and tissue oxygen tensions during crystalloid resuscitation from hemorrhagic shock. DESIGN: Randomized, control trial. SETTING: An animal laboratory at a university center. SUBJECTS: Twelve piglets, mean weight 22 kg. INTERVENTIONS: The animals were anesthetized and bled to a state of hemorrhagic shock and resuscitated, using a crystalloid solution infused at a rate of approximately 2.6 mL/min/kg (total amount 208 mL/kg). Cardiac output and mean arterial pressure (MAP were measured as indicators of volume filling during the 20- to 30-min resuscitation period and during the follow-up period until 80 mins from the start of resuscitation. Dopexamine was administered by infusion at 6 micrograms/kg-min from the start of volume replacement (dopexamine group, n = 6). The rest of the animals (control group, n = 6) were given volume replacement only. MEASUREMENTS AND MAIN RESULTS: Systemic oxygen transport variables were calculated. Tissue oxygen tensions were continuously recorded from the liver, conjunctival layer, and via subcutaneous and transcutaneous electrodes in the abdominal region. MAP decreased from 119 +/- 2 (SEM) to 44 +/- 2 mm Hg and cardiac output decreased by 77% during the shock period. During resuscitation, cardiac output was restored in both groups. MAP increased close to the baseline during the early resuscitation period and decreased slowly during follow-up. Oxygen delivery remained at 46% of baseline, whereas systemic oxygen consumption was restored during resuscitation in both groups. Liver tissue oxygen tension increased well above baseline during resuscitation in the dopexamine group, and liver tissue oxygen tension was significantly higher than in the control group. After 60 mins of resuscitation, the liver oxygen tension decreased to control group values. None of the other tissue oxygen tensions showed any differences between groups. CONCLUSIONS: Dopexamine administration during crystalloid resuscitation from hemorrhagic shock was well tolerated and resulted in significant and specific, although transient, improvement in liver oxygenation.     

Early activation of vascular endothelium in nonobese, nondiabetic essential hypertensive patients with multiple metabolic abnormalities

OBJECTIVES: Inhibitors of nitric oxide synthesis have been suggested to be of value in the treatment of hypotension during sepsis. However, earlier clinical reports only describe the initial effects of these nitric oxide inhibitors. This study was designed to examine the effects of the prolonged inhibition of nitric oxide synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock. DESIGN: Prospective, nonrandomized, clinical study. SETTING: Medical-surgical intensive care unit in a university hospital. PATIENTS: Eleven consecutive patients with ongoing hyperdynamic septic shock that was unresponsive to fluid resuscitation and vasopressor therapy. INTERVENTIONS: Measurements of hemodynamic, hematologic, and biochemical variables were made before, during, and after the start of a continuous intravenous infusion of 1 mg/kg/hr of L-NAME, an inhibitor of nitric oxide synthesis, for a period of 12 hrs. MEASUREMENTS AND MAIN RESULTS: Continuous infusion of L-NAME resulted in a direct increase in mean arterial pressure from 65 +/- 3 (SEM) to 93 +/- 4 mm Hg and an increase in systemic vascular resistance from 426 +/- 54 to 700 +/- 75 dyne x sec/cm5, reaching a maximum at 0.5 hr. Pulmonary arterial pressure was increased from 31 +/- 2 to a maximum of 36 +/- 2 mm Hg at 1 hr, and pulmonary vascular resistance increased from 146 +/- 13 to a maximum of 210 +/- 23 dyne x sec/cm5 at 3 hrs. Paralleling these changes, cardiac output decreased from 10.8 +/- 0.8 to 8.7 +/- 0.7 L/min and oxygen delivery decreased from 1600 +/- 160 to 1370 +/- 130 mL/min (for all changes p < .05 as compared with the baseline value). Heart rate, cardiac filling pressures, oxygen consumption, urine production, arterial lactate concentration, and other biochemical parameters were not significantly changed by L-NAME administration (all p > .05). Arterial oxygenation was improved during L-NAME infusion, and the dosage of catecholamines could be reduced (both p< .05). Although sustained hemodynamic effects were seen, L-NAME was most effective during the early stages of administration, and the effect of L-NAME on blood pressure and vascular resistance tended to diminish throughout the continuous infusion of L-NAME. Seven of 11 patients ultimately died, with survival time ranging from 2 to 34 days. CONCLUSIONS: Nitric oxide appears to play a role in cardiovascular derangements during human sepsis. The increased blood pressure and vascular resistance values are sustained during prolonged inhibition of nitric oxide synthesis with L-NAME in patients with severe septic shock, although the hemodynamic changes are most significant in the early stages of L-NAME infusion. The high mortality rate in these patients may suggest that L-NAME has only limited effects on outcome.     

Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock

OBJECTIVE: The aim of this study was to investigate the acute effects of methylene blue (MB), an inhibitor of the L-arginine nitric oxide pathway, in patients with septic shock. DESIGN: A prospective, open, single-dose study. SETTING: The medical ICU of a university hospital. PATIENTS: Six patients with severe septic shock. INTERVENTIONS: Complete hemodynamic values were recorded before and 20 min after the infusion of intravenous MB (3 mg kg(-1)). Arterial pressure was then monitored during the next 24 h or until death. MEASUREMENTS AND RESULTS: Methylene blue increased the mean arterial pressure from 69.7 +/- 4.5 to 83.7 +/- 5.1 mmHg (p = 0.028) and the mean pulmonary artery pressure, from 34.3 +/- 7.2 to 38.7 +/- 8.0 mmHg (p = 0.023). Systemic vascular resistance index was increased from 703.1 +/- 120.6 to 903.7 +/- 152.2 dyne.s.cm(-5).m(-2) (p = 0.028) and pulmonary vascular resistance index, from 254.6 +/- 96.9 to 342.2 +/- 118.9 dyne.s.cm(-5) .m(-2) (p = 0.027). The PaO2/FIO2 decreased from 229.2 +/- 54.4 to 162.2 +/- 44.1 mmHg (p = 0.028), without significant modification of intrapulmonary shunting. Heart rate, cardiac index, right atrial pressure, DO2, VO2, oxygen extraction and arterial lactate were essentially unchanged. Sequential measurements of arterial pressure demonstrated a return to baseline level in 2-3 h. All but one patients died, three in shock and two in multiple organ failure. CONCLUSIONS: MB induces systemic and pulmonary vasoconstriction in patients with septic shock, without significant decrease in cardiac index. The worsening of arterial oxygenation following MB injection may limit its use in patients with the adult respiratory distress syndrome. Larger studies are required to determine whether MB improves the outcome of patients with septic shock.     

Effects of nitro-L-arginine on blood pressure and cardiac index in anesthetized rats: a pharmacokinetic-pharmacodynamic analysis

PURPOSE: Nitric oxide synthase (NOS) inhibitors such as Nitro-L-arginine (L-NA) are being considered for the management of hypotension observed in septic shock. However, little information is available regarding the pharmacokinetic and pharmacodynamic properties of these agents. Our objective was to examine the relationships between L-NA plasma concentration and various hemodynamic effects such as cardiac index (CI), mean arterial pressure (MAP), and heart rate (HR) elicited by L-NA administration in rats. METHODS: L-NA was infused at doses between 2.5-20 mg/kg/hr in anesthetized rats over one hour. Hemodynamic effects and plasma L-NA levels were determined. RESULTS: Infusion of L-NA resulted in dose-dependent increases in MAP and systemic vascular resistance (SVR), decreases in CI, and minimal change in HR. The relationships between the hemodynamic effects and plasma L-NA levels were not monotonic, and hysteresis was observed. Using nonparametric analysis, the equilibration half-time (t1/2,keo) between plasma L-NA and the hypothetical effect site was determined to be 51.5 +/- 6.6 min, 42.4 +/- 10.1 min, 43.4 +/- 9.0 min for MAP, CI, and SVR, respectively (n = 14). The Emax and EC50 values obtained were + 32.5 +/- 8.4 and 2.6 +/- 1.3 microg/ml for MAP and -52.9 +/- 15.6 and 3.7 +/- 1.8 microg/ml for CI, respectively. CONCLUSIONS: Although L-NA can bring about beneficial elevation of MAP, such effect is always accompanied by a stronger effect on CI depression. Dose escalation of L-NA may bring about detrimental negative inotropic effect and loss of therapeutic efficacy.     

Circulating methemoglobin and nitrite/nitrate concentrations as indicators of nitric oxide overproduction in critically ill children with septic shock

OBJECTIVES: To examine the relationship between circulating methemoglobin and nitrite/nitrate concentrations and to compare these markers of nitric oxide overproduction with clinical variables in children diagnosed with septic shock. DESIGN: Prospective, controlled, clinical study. SETTING: Pediatric intensive care unit and outpatient clinic in a children's hospital. PATIENTS: Twenty-two children diagnosed with septic shock and ten age-matched healthy control patients. INTERVENTIONS: Patients diagnosed with septic shock had blood specimens taken on study entry and every 6 hrs for 72 hrs for methemoglobin and nitrite/nitrate determinations. Single blood specimens were obtained from controls. MEASUREMENTS AND MAIN RESULTS: Circulating methemoglobin and nitrite/nitrate concentrations were significantly higher in children diagnosed with septic shock in comparison with healthy control children (p = .01 and .05, respectively). Peak nitrite/nitrate concentrations correlated with serum creatinine (r2 = .19; p = .04) and were inversely correlated with arterial pH (r2 = .28; p = .01) and urine output (r2 = .21; p = .03) when analyzed by log-linear regression. There were no significant relationships between methemoglobin and nitrite/nitrate or between methemoglobin and any other clinical variable. CONCLUSIONS: Circulating methemoglobin and nitrite/nitrate concentrations are increased in children diagnosed with septic shock. Plasma nitrite/nitrate values correlate with selected clinical variables in these children. Circulating methemoglobin measurements are not superior to plasma nitrite/nitrate concentrations as an indicator of endogenous overproduction of nitric oxide in children diagnosed with septic shock. A need remains to develop markers of endogenous nitric oxide activity that have greater accuracy and reliability.     

Changes in plasma erythropoietin and interleukin-6 concentrations in patients with septic shock after hemoperfusion with polymyxin B-immobilized fiber

OBJECTIVE: To find out whether polymyxin B-immobilized fiber (PMX-F) treatment affects the clinical parameters and plasma concentrations of erythropoietin (EPO) and interleukin (IL)-6. DESIGN: A prospective case series study. SETTING: Intensive care unit of the Department of Internal Medicine, Misato Junshin Hospital, Saitama, and Koto Hospital, Tokyo, Japan. PATIENTS: 17 consecutive patients (10 men, 7 women; mean age 54.6 years) with clinically defined septic shock and 20 healthy volunteers (12 men, 8 women; mean age 52.2 years). MAIN RESULTS: Of the 17 patients with septic shock, 9 (53 %) survived. The systolic blood pressure increased significantly from 78+/-6 to 106+/-8 mm Hg 2 h after PMX-F treatment in patients with septic shock. Plasma endotoxin levels decreased significantly after treatment, from 40+/-6 to 12+/-4 pg/ml. The pretreatment plasma concentrations of EPO and IL-6 were significantly higher in the 8 nonsurviving patients with septic shock (EPO: 400+/-36 mlU/ml; IL-6: 6260+/-1180 pg/ml) than in the 9 surviving patients (EPO: 120+/-22 mlU/ml; IL-6: 680+/-138 pg/ml) and the 20 control subjects (EPO, 12+/-6 mlU/ml; IL-6, 8+/-2 pg/ml). Plasma concentrations of EPO and IL-6 in patients with septic shock decreased significantly after PMX-F treatment (EPO, nonsurviving: 320+/-28 mlU/ml, p < 0.05; survivors: 26+/-8 mlU/ ml, p < 0.001; IL-6, nonsurviving: 3860+/-840 pg/ml, p < 0.01; survivors: 84+/-20 pg/ml, p < 0.001). CONCLUSIONS: Plasma concentrations of EPO and IL-6 may be prognostic indicators in patients with septic shock: PMX-F treatment may be effective in reducing the plasma concentrations of EPO and IL-6 in patients with septic shock.     

N(G)-monomethyl-L-arginine improves survival in a pig model of abdominal sepsis

OBJECTIVE: To test the effect of a continuous infusion of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on survival rate and hemodynamics in a pig model of endogenous peritoneal live bacterial sepsis. DESIGN: Prospective, randomized trial. SETTING: Laboratory at a university medical center. SUBJECTS: Thirty-five pigs with an average weight of 26 kg (range 21 to 33). INTERVENTIONS: After surgical preparation, animals (control, n=6) given anesthesia and fluids were observed for 9 hrs. Fifteen experimental animals received 0.5 g of cecal content/kg of body weight intraperitoneally after surgery. Nine of these animals received standard anesthesia and fluids and were observed for 9 hrs or until death. Six animals received a continuous infusion of L-NMMA (10 mg/kg/hr) 3 hrs after sepsis induction. Starting 3 hrs after surgery, five nonrandomized animals were given anesthesia and fluids and received a 6-hr continuous infusion of L-NMMA (10 mg/kg/hr). An additional nine animals were anesthetized and blood samples were taken to determine plasma nitrate concentrations in nonoperated pigs. MEASUREMENTS AND MAIN RESULTS: L-NMMA treatment increased 9-hr survival in septic animals from 11% to 83% (p < .001), prevented a further decrease in mean arterial pressure and restored mean arterial pressure to control levels (p < .00002 vs. nontreated septic animals). Mean pulmonary arterial pressure increased slightly during L-NMMA infusion (p < .0003). Coronary blood flow was preserved during L-NMMA treatment. Cardiac index and urine production reached and maintained control levels during L-NMMA treatment of septic animals. Mean central venous pH did not deteriorate during L-NMMA treatment. Animals treated with L-NMMA had plasma nitrate concentrations similar to nonseptic control animals. The results from the nonseptic control group receiving L-NMMA suggest that a substantial part of the effect of L-NMMA in this model of septic shock may be due to inhibition of the constitutive nitric oxide production. CONCLUSIONS: In this porcine model of peritoneal sepsis, infusion of L-NMMA increased survival rate and maintained mean arterial pressure without worsening tissue oxygenation. Coronary blood flow, cardiac index, systemic vascular resistance, and urine production were well maintained during L-NMMA treatment.     

The effects of intravenous antioxidants in patients with septic shock

Oxidative stress is implicated in septic shock. We investigated the effect of intravenous antioxidant therapy on antioxidant status, lipid peroxidation, hemodynamics and nitrite in patients with septic shock. Thirty patients randomly received either antioxidants (n-acetylcysteine 150 mg/kg for 30 min then 20 mg/kg/h plus bolus doses of 1 g ascorbic acid and 400 mg alpha-tocopherol) or 5% dextrose. Basal vitamin C was low and redox-reactive iron was elevated in all patients. In the 16 patients receiving antioxidants, vitamin C increased (p = .0002) but total antioxidant capacity was unaffected. Lipid peroxides were elevated in all patients but did not increase further in the patients receiving antioxidants. Plasma total nitrite also increased (p = .007) in the antioxidant group. Heart rate increased in patients receiving antioxidants at 60 min (p = .018) and 120 min (p = .004). Cardiac index also increased at 60 min (p = .007) and 120 min (p = .05). Systemic vascular resistance index decreased at 120 min in the antioxidant treated patients (p = .003). The effect of antioxidants on hemodynamic variables has not previously been reported. Antioxidant administration may be a useful adjunct to conventional approaches in the management of septic shock.     

Effect of dehydroepiandrosterone sulfate on uterine artery flow velocity waveforms in term pregnancy

OBJECTIVE: To investigate the interrelation between estrogen synthesis by the fetoplacental unit and uteroplacental hemodynamics in term pregnancy. METHODS: Transvaginal color Doppler flow imaging and pulsed Doppler ultrasonographic assessments were made on ten normal full-term pregnant women before and 3, 5, 10, 30, and 60 minutes after the administration of a 200-mg intravenous dose of dehydroepiandrosterone sulfate (DHAS) in 20 mL of 5% dextrose. Ten normal full-term pregnant women received 20 mL of 5% dextrose as controls. The pulsatility index (PI) values for the uterine artery, heart rate, and mean arterial pressure were recorded. Plasma estradiol (E2) was measured before and 10 minutes after the infusion. RESULTS: In the DHAS group, uterine artery PI decreased from baseline by 26% (P < .05) after 5 minutes, and the mean reduction was 36% (P < .05) after 10 minutes and 15% (P < .05) after 30 minutes. The PI returned to the baseline value 60 minutes later. In the control group, there was no change in uterine artery PI. No change was found in heart rate or mean arterial blood pressure in the control or DHAS groups. The mean plasma E2 increased from 22.3 +/- 6.6 to 56.2 +/- 24.1 ng/mL (P < .05) 10 minutes after the infusion in DHAS subjects, whereas there was no significant change in plasma E2 in the controls. CONCLUSION: Dehydroepiandrosterone sulfate induces a significant decrease in the uterine artery PI, which suggests a possible decrease in uterine vascular impedance in term pregnancy.