Risks of restrictive red blood cell transfusion strategies in patients with cardiovascular disease (CVD): a meta-analysis.

AIM: To evaluate the risks of restrictive red blood cell transfusion strategies (haemoglobin 7-8 g dL-1 ) in patients with and without known cardiovascular disease (CVD). BACKGROUND: Recent guidelines recommend restrictive strategies for CVD patients hospitalised for non-CVD indications, patients without known CVD and patients hospitalised for CVD corrective procedures. METHODS/MATERIALS: Database searches were conducted through December 2017 for randomised clinical trials that enrolled patients with and without known CVD, hospitalised either for CVD-corrective procedures or non-cardiac indications, comparing effects of liberal with restrictive strategies on major adverse coronary events (MACE) and death. RESULTS: In CVD patients not undergoing cardiac interventions, a liberal strategy decreased (P = 0·01) the relative risk (95% CI) (RR) of MACE [0·50 (0·29-0·86)] (I2  = 0%). Among patients without known CVD, the incidence of MACE was lower (1·7 vs 3·9%), and the effect of a liberal strategy on MACE [0·79, (0·39-1·58)] was smaller and non-significant but not different from CVD patients (P = 0·30). Combining all CVD and non-CVD patients, a liberal strategy decreased MACE [0·59, (0·39-0·91); P = 0·02]. Conversely, among studies reporting mortality, a liberal strategy decreased mortality in CVD patients (11·7% vs·13·3%) but increased mortality (19·2% vs 18·0%) in patients without known CVD [interaction P = 0·05; ratio of RR 0·73, (0·53-1·00)]. A liberal strategy also did not benefit patients undergoing cardiac surgery; data were insufficient for percutaneous cardiac procedures. CONCLUSIONS: In patients hospitalised for non-cardiac indications, liberal transfusion strategies are associated with a decreased risk of MACE in both those with and without known CVD. However, this only provides a survival benefit to CVD patients not admitted for CVD-corrective procedures.

The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis.

A previous meta-analysis determined that the effects of steroids during sepsis were dose-dependent; since then, additional trials have been published. The current analysis updates our previous analysis examining the effects of steroids during sepsis. A literature search from 2004 to 2008 identified seven randomized controlled trials in adult patients; these were added to 14 previously identified trials. The effects of steroids on mortality were highly variable among the 21 trials (p <0.001, I(2) = 60%). In trials published before 1989, which involved short courses of high-dose steroids, steroids increased mortality (n = 8, I(2) = 14%, OR of death 1.39 (95% CI 1.04-1.86), p 0.03). In trials published after 1997, which involved longer courses of lower-dose steroids, steroids consistently improved shock reversal (n = 7, I(2) = 0%, OR of shock reversal 1.66 [95% CI 1.25-2.20), p <0.001), but demonstrated a more heterogeneous beneficial effect on mortality (n = 12, I(2) = 25%, OR of death 0.64 (95% CI 0.45-0.93), p 0.02). An inverse linear relationship between severity of illness and the effects of steroids on mortality was identified across all trials (p 0.03) and within the subgroup of trials published after 1997 (p 0.03); steroids were harmful in less severely ill patient populations and beneficial in more severely ill patient populations. There was no effect of response to adrenocorticotrophic hormone (ACTH) stimulation testing concerning the effects of steroids and no increase in steroid-associated adverse events. Low-dose steroids appear to improve mortality rates in patients with septic shock who are at high risk of death; however, additional trials in this subpopulation are necessary to definitively determine the role of low-dose steroids during sepsis.

Increasing the efficacy of anti-inflammatory agents used in the treatment of sepsis.

Excessive production of inflammatory mediators during invasive infection plays a key role in the pathogenesis of septic shock. In an attempt to improve survival of patients with this lethal syndrome, agents were developed to selectively inhibit mediators in this inflammatory response. Despite promising preclinical results, several different mediator-specific anti-inflammatory agents failed to demonstrate significant benefit in patients. There was, however, a significant difference in mortality between preclinical and clinical trials. The median control mortality in preclinical trials, performed almost uniformly in highly lethal sepsis models, was 88%. In clinical trials however, the median control mortality rate was much lower, at 41%. A recent meta-regression analysis of these preclinical and clinical trials in combination with prospective confirmatory studies demonstrated that risk of death as assessed by control group mortality rate significantly altered the treatment effect of these agents in both humans and animals. While anti-inflammatory agents were very beneficial in groups with high control mortality rates, they were ineffective or harmful in groups with low control mortality rates. Thus, variation in the risk of death due to sepsis provides a basis for the marked difference in the efficacy of these anti-inflammatory agents in preclinical and clinical trials over the last decade. In contrast to mediator-specific anti-inflammatory agents, glucocorticoids and activated protein C have recently demonstrated significant beneficial effects in individual clinical trials. However, glucocorticoids were studied only in patients with vasopressor-dependent septic shock, which is associated with a high control mortality rate (i.e. 61%) similar to the level at which mediator-specific agents would have been expected to be markedly beneficial. Furthermore, consistent with earlier findings for mediator-specific anti-inflammatory agents, analysis of the activated protein C study also demonstrated a relationship between risk of death and effect of treatment. Developing better methods to define high-risk septic populations for treatment with anti-inflammatory agents will increase the efficacy of this therapeutic approach and minimize its potential for harm.

Acute G-CSF therapy is not protective during lethal E. coli sepsis.

We investigated whether decreases in circulating polymorphonuclear neutrophils (PMN) during lethal Escherichia coli (E. coli) sepsis in canines are related to insufficient host granulocyte colony-stimulating factor (G-CSF). Two-year-old purpose-bred beagles had intraperitoneal E. coli-infected or -noninfected fibrin clots surgically placed. By 10 to 12 h following clot, both infected survivors and nonsurvivors had marked increases (P = 0.001) in serum G-CSF levels (mean peak G-CSF ng/ml +/- SE, 1,931 +/- 364 and 2,779 +/- 681, respectively) compared with noninfected controls (134 +/- 79), which decreased at 24 to 48 h. Despite increases in G-CSF, infected clot placement caused delayed (P = 0.06) increases in PMN (mean +/- SE change from baseline in cells x 10(3)/mm(3) at 24 and 48 h) in survivors (+3.9 +/- 3.9 and +13.8 +/- 3.6) compared with noninfected controls (+13.1 +/- 2.8 and +9.1 +/- 2.5). Furthermore, infected nonsurvivors had decreases in PMN (-1.4 +/- 1.0 and -1.1 +/- 2.3, P = 0.006 compared with the other groups). We next investigated whether administration of G-CSF immediately after clot placement and continued for 96 h to produce more rapid and prolonged high levels of G-CSF after infection would alter PMN levels. Although G-CSF caused large increases in PMN compared with control protein from 2 to 48 h following clot in noninfected controls, it caused much smaller increases in infected survivors and decreases in infected nonsurvivors (P = 0.03 for the ordered effect of G-CSF comparing the three groups). Thus insufficient host G-CSF is unlikely the cause of decreased circulating PMN in this canine model of sepsis. Other factors associated with sepsis either alone or in combination with G-CSF itself may reduce increases or cause decreases in circulating PMN.

ICAM-1 and CD11b inhibition worsen outcome in rats with E. coli pneumonia.

We investigated whether inhibiting an endothelial adhesion molecule [intracellular adhesion molecule 1 (ICAM-1)] would alter outcome and lung injury in a similar fashion to inhibition of a leukocyte adhesion molecule (integrin CD11b) in a rat model of gram-negative pneumonia. Inhibition of ICAM-1 with monoclonal antibody (MAb) 1A29 (1 mg/kg sc or 0.2 or 2 mg/kg iv, q 12 h x 3) or of CD11b with MAb 1B6 (1 mg/kg sc, q 12 h x 3) were compared against similarly administered placebo proteins in rats challenged with intrabronchial Escherichia coli. After challenge, all animals were treated with antibiotics. ICAM-1 MAb (6 mg/kg, iv, total dose) increased mortality vs. control (P = 0.03). CD11b MAb (3 mg/kg, sc, total dose) did not significantly (P = 0.16) increase mortality rates, but this was not in a range of probability to exclude a harmful effect. All other doses of MAb had no significant effect on survival rates. ICAM-1 and CD11b MAbs had significantly different effects on the time course of lung injury, circulating white cells and lymphocytes, and lung lavage white cells and neutrophils (P = 0.04-0.003). CD11b MAb decreased, whereas ICAM-1 MAb increased these measures compared with control from 6 to 12 h after E. coli. However, from 144 to 168 h after E. coli both MAbs increased these measures compared with control rats but to a greater level with CD11b MAb. Thus both ICAM-1 and CD11b appear to be necessary for survival during E. coli pneumonia. Although these adhesion molecules may participate differently in early lung injury, with CD11b increasing and ICAM-1 decreasing inflammation and injury, both are important for the resolution of later injury. During gram-negative pneumonia the protective roles of ICAM-1 and CD11b may make their therapeutic inhibition difficult.

Neutrophil and endothelial cell interactions in sepsis. The role of adhesion molecules.

Although adhesion molecules present on circulating neutrophils and endothelial cells are essential for normal host defense, generalized activation of these molecules has been implicated in the inflammatory tissue injury occurring during sepsis and septic shock. A review of both preclinical and clinical studies suggests, however, that although these molecules mediate tissue injury related to a variety of microbial and host inflammatory mediators, their predominant role during sepsis with infection is a protective one.

G-CSF during Escherichia coli versus Staphylococcus aureus pneumonia in rats has fundamentally different and opposite effects.

We investigated if bacteria type alters outcome with prophylactic granulocyte colony stimulating factor (G-CSF) therapy during pneumonia. Rats received G-CSF or placebo daily for 6 d and after the third dose were intrabronchially inoculated with either Escherichia coli or Staphylococcus aureus. Without G-CSF, E. coli and S. aureus produced similar (p = NS) mortality rates (36 versus 38%) and serial changes in mean circulating neutrophil counts (CNC), but differing mean (+/- SE) tumor necrosis factor (TNF) levels (E. coli, 259 +/- 104 versus S. aureus, 51 +/- 17 pg/ml, p = 0.01). G-CSF prior to bacteria increased mean CNC more than six times compared with placebo (p = 0.001). However, with G-CSF in the first 6 h after E. coli, there was a greater than 20-fold decrease in mean (+/- SE) CNC (x 10(3)/ mm3) to below placebo (0.5 +/- 0.1 versus 0.8 +/- 0.1), whereas with G-CSF after S. aureus, there was only a fivefold decrease in mean CNC and CNC were greater than placebo (1.8 +/- 0.2 versus 0.8 +/- 0.1) (E. coli versus S. aureus decrease in CNC with G-CSF, p = 0.001). With E. coli, G-CSF worsened oxygenation and increased bacteremia and mortality, whereas with S. aureus, G-CSF improved oxygenation and decreased bacteremia and mortality (G-CSF therapy, E. coli versus S. aureus, p = 0.03, 0.05, and 0.001, respectively). Thus, during S. aureus pneumonia with low TNF levels, G-CSF increased CNC and bacterial clearance, resulting in less pulmonary injury and decreased death. During E. coli pneumonia with high TNF levels, G-CSF paradoxically decreased CNC, resulting in impaired bacterial clearance and worsened pulmonary injury and death. Bacterial species and the associated inflammatory mediator response can alter outcome with prophylactic G-CSF therapy during pneumonia.

Increasing doses of pentoxifylline as a continuous infusion in canine septic shock.

We investigated effects of pentoxifylline during septic shock. Two-year-old (10-12 kg), purpose-bred beagles were infected i.p. with Escherichia coli 0111:B4 (1.2-1.5 x 10(9) colony-forming units per kilogram b.wt.) in a fibrin clot and then immediately treated with one of five doses of pentoxifylline (0.5-20 mg. kg-1. h-1 i.v.) as a 36-h continuous infusion or placebo. All animals received antibiotics and fluid resuscitation. Pentoxifylline levels increased in a dose-dependent manner during (p =.001) and were undetectable 12 h after stopping the infusion. During infusion of pentoxifylline at all doses, there were increases (p =.003), and once the infusion was stopped, there were decreases (p =.049) in endotoxin levels compared with controls. After clot implantation, at all pentoxifylline doses there was a significant increase in tumor necrosis factor levels, compared with controls (p =.025). The relative risk of death was significantly increased with pentoxifylline therapy in a dose-dependent fashion (20 >/= 10 >/= 5.0 >/= 1.0 >/= 0.5 mg. kg-1, p =.008). One hypothesis consistent with these data is that high pentoxifylline levels slowed endotoxin clearance, resulting in high levels of endotoxemia and increased proinflammatory mediator release and death. Pentoxifylline, used as a long-term continuous infusion as is commonly done clinically, can be harmful during Gram-negative septic shock.

Effects of L-NMMA and fluid loading on TNF-induced cardiovascular dysfunction in dogs.

We investigated the effects of N(omega)-monomethyl-L-arginine (L-NMMA) and fluid loading on tumor necrosis factor (TNF)-induced cardiovascular dysfunction in awake dogs. L-NMMA (40 mg x kg(-1) given intravenously over a period of 10 min, and followed by dosing at 40 mg x kg(-1) x h(-1) for 6 h) and TNF (20 or 45 microg x kg(-1) given intravenously for 20 min), given alone or in combination, significantly decreased stroke volume, cardiac index, oxygen delivery, and left-ventricular (LV) function plots over a period of 6 h. Of note was that the cardiac-depressant effects of TNF and L-NMMA given together were significantly less than additive. Thus, the combination was beneficial (or significantly less harmful to cardiac performance than expected), possibly because L-NMMA augmented cardiac preload as shown by significant increases in both pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP). Fluid challenges at 6 h (Ringer's solution at 80 ml x kg(-1) given over a period of 30 min) also significantly increased PCWP and CVP, and abolished the beneficial preload effect of L-NMMA on cardiac performance. Thus, after fluid loading, the cardiac-depressant effects of TNF and L-NMMA given together became equal to the sum of those produced by TNF and L-NMMA given separately. Although L-NMMA significantly decreased serum nitrite/nitrate levels, TNF did not increase these end products of nitric oxide (NO) production relative to controls. Therefore, after preload abnormalities were eliminated with fluid loading, L-NMMA had no beneficial effect on TNF-induced cardiac depression, and TNF did not increase end products of NO production. These findings are not consistent with NO being the mechanism of TNF-induced acute cardiac depression.

Response of the septic vasculature to prolonged vasopressor therapy with N(omega)-monomethyl-L-arginine and epinephrine in canines.

OBJECTIVE: To investigate the effect of blocking nitric oxide production on cardiovascular function and survival in canine septic shock treated with or without a conventional vasopressor. DESIGN: Randomized, controlled trial. SETTING: An animal research laboratory at the National Institutes of Health. SUBJECTS: Sixty purpose-bred beagles. INTERVENTIONS: Fibrin clots containing Escherichia coli were surgically placed into the peritoneal cavity. N(omega)-monomethyl-L-arginine (L-NMMA) 10 mg/kg followed by 0.5, 1.0, or 4.0 mg/kg/hr), epinephrine (1 microg/kg/min), both, or neither were infused for 24 hrs beginning 6 hrs after the onset of infection. All animals received fluid and antibiotic therapy. MEASUREMENTS AND MAIN RESULTS: Serum nitric oxide metabolites, nitrite and nitrate, increased with infection (p = .024) and decreased with L-NMMA (p = .004, all doses combined). Myocardial nitric oxide synthase activity was ranked as follows: nonsurvivors > survivors > noninfected controls (p < .01). Other tissues examined showed the same pattern. L-NMMA produced sustained increases in systemic vascular resistance index and mean arterial pressure 9 and 24 hrs after the onset of infection (p < or = .04). Left ventricular ejection fraction was depressed by septic shock (p = .01) and further decreased by L-NMMA (p = .02). However, control and L-NMMA cardiac index values were similar (p > .4), perhaps because L-NMMA increased pulmonary artery occlusion pressure (p = .02). From 9 to 24 hrs, epinephrine, in the absence or presence of L-NMMA, blunted recovery of cardiac index (p < .02) and had a diminishing vasopressor effect (p = .05). Neither L-NMMA nor epinephrine, individually or combined, significantly altered survival rates at the doses investigated (p > or = .69). CONCLUSIONS: The tested doses showed that nitric oxide production was inhibited by L-NMMA in canine septic shock, but mortality and myocardial depression were unaffected. These results suggest that if L-NMMA has a beneficial effect on survival rates in septic shock, it is small.

Cardiopulmonary effects of inhaled nitric oxide in normal dogs and during E. coli pneumonia and sepsis.

We investigated the effect of inhaled nitric oxide (NO) at increasing fractional inspired O2 concentrations (FIO2) on hemodynamic and pulmonary function during Escherichia coli pneumonia. Thirty-eight conscious, spontaneously breathing, tracheotomized 2-yr-old beagles had intrabronchial inoculation with either 0.75 or 1.5 x 10(10) colony-forming units/kg of E. coli 0111:B4 (infected) or 0.9% saline (noninfected) in one or four pulmonary lobes. We found that neither the severity nor distribution (lobar vs. diffuse) of bacterial pneumonia altered the effects of NO. However, in infected animals, with increasing FIO2 (0.08, 0.21, 0.50, and 0.85), NO (80 parts/million) progressively increased arterial PO2 [-0.3 +/- 0.6, 3 +/- 1, 13 +/- 4, 10 +/- 9 (mean +/- SE) Torr, respectively] and decreased the mean arterial-alveolar O2 gradient (0.5 +/- 0.3, 4 +/- 2, -8 +/- 7, -10 +/- 9 Torr, respectively). In contrast, in noninfected animals, the effect of NO was significantly different and opposite; NO progressively decreased mean PO2 with increasing FIO2 (2 +/- 1, -5 +/- 3, -2 +/- 3, and -12 +/- 5 Torr, respectively; P < 0.05 compared with infected animals) and increased mean arterial-alveolar O2 gradient (0.3 +/- 0.04, 2 +/- 2, 1 +/- 3, 11 +/- 5 Torr; P < 0.05 compared with infected animals). In normal and infected animals alike, only at FIO2 < or = 0.21 did NO significantly lower mean pulmonary artery pressure, pulmonary artery occlusion pressure, and pulmonary vascular resistance index (all P < 0.01). However, inhaled NO had no significant effect on increases in mean pulmonary artery pressure associated with bacterial pneumonia. Thus, during bacterial pneumonia, inhaled NO had only modest effects on oxygenation dependent on high FIO2 and did not affect sepsis-induced pulmonary hypertension. These data do not support a role for inhaled NO in bacterial pneumonia. Further studies are necessary to determine whether, in combination with ventilatory support, NO may have more pronounced effects.

Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial products and TNF. Using a canine model of gram-negative septic shock, we investigated the effect of tyrosine kinase inhibitors (tyrphostins) on survival. Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated immediately with one of two tyrphostins, AG 556 (n = 40) or AG 126 (n = 10), or with control (n = 50), and followed for 28 d or until death. All animals received supplemental oxygen, fluids, and antibiotics. Tyrphostin AG 556 improved survival times when compared to controls (P = 0.05). During the first 48 h after infection, AG 556 also improved mean arterial pressure, left ventricular ejection fraction, cardiac output, oxygen delivery, and alveolar-arterial oxygen gradient compared to controls (all P < or = 0.05). These improvements in organ injury were significantly predictive of survival. Treatment with AG 556 had no effect on clearance of endotoxin or bacteria from the blood (both P = NS); however, AG 556 did significantly lower serum TNF levels (P = 0.03). These data are consistent with the conclusion that AG 556 prevented cytokine-induced multiorgan failure and death during septic shock by inhibiting cell-signaling pathways without impairing host defenses as determined by clearance of bacteria and endotoxin.

rG-CSF reduces endotoxemia and improves survival during E. coli pneumonia.

We investigated the effects of recombinant granulocyte colony-stimulating factor (rG-CSF) during canine bacterial pneumonia. Beagles with chronic tracheostomies received daily subcutaneous rG-CSF (5 micrograms/kg body wt) or placebo for 14 days, beginning 9 days before intrabronchial inoculation with E. coli. Animals received antibiotics and fluid support; a subset received humidified oxygen (fractional inspired O2 0.40). Compared with controls, rG-CSF increased circulating neutrophil counts (57.4 vs. 11.0 x 10(3)/mm3, day 1 after infection; P = 0.0001), decreased plasma endotoxin (7.5 vs. 1.1 EU/ml at 8 h; P < 0.01) and serum tumor necrosis factor-alpha (3,402 vs. 729 pg/ml at 2 h; P = 0.01) levels, and prolonged survival (relative risk of death = 0.45, 95% confidence interval 0.21-0.97; P = 0.038). Also, rG-CSF attenuated sepsis-associated myocardial dysfunction (P < 0.001). rG-CSF had no effect on pulmonary function or on blood and lung bacteria counts (all P = not significant). Other animals challenged with endotoxin (4 mg/kg i.v.) after similar treatment with rG-CSF had lower serum endotoxin levels (7.62 vs. 5.81 log EU/ml at 6 h; P < 0.01) and less cardiovascular dysfunction (P < 0.05 to < 0.002) but similar tumor necrosis factor-alpha levels (P = not significant) compared with controls. Thus prophylactic rG-CSF sufficient to increase circulating neutrophils during bacterial pneumonia may improve cardiovascular function and survival by mechanisms that in part enhance the clearance of bacterial toxins but do not improve lung function.

Serial measures of total body oxygen consumption in an awake canine model of septic shock.

We examined serial changes in total body oxygen consumption (Vo2) in a permanently tracheotomized canine sepsis model. On Day 0, beagles had an Escherichia coli-infected (septic) or sterile (control) clot surgically placed in the peritoneum. During the 21-d study, 10 of the 16 septic animals and none of the six control animals died (p = 0.02). After clot placement septic versus control animals had decreased mean arterial blood pressure (mm Hg; Day 1: 106 versus 128, p = 0.055; Day 2: 95 versus 125, p = 0.004, respectively) and left ventricular ejection fraction (Day 1: 0.44 versus 0.69, p = 0.0006; Day 2: 0.33 versus 0.57, p = 0.0001, respectively). Despite significant lethality and cardiovascular dysfunction, in the septic group on Days 1 and 2, septic versus control animals had no significant differences in mean metabolic cart measured (Vo2DIR, ml/kg/min; Day 1: 11.9 versus 12.4, p = 0.81; Day 2: 14.2 versus 13.5, p = 0.72, respectively) and intravascular catheter calculated (Vo2INDIR, ml/kg/min; Day 1: 11.2 versus 11.2, p = 0.99; Day 2: 12.8 versus 15.4, p = 0.49, respectively). On Day 1 in septic and control animals, volume infusion produced increases (p < 0.001) in oxygen delivery (Do2). In septic and control animals these changes in Do2 were similar and were associated with similar increases in Vo2DIR (p = 0.001), and Vo2INDIR (p = 0.001). In fact, at all time points studied (baseline, Day 1, 2, and 21), both before and after volume infusion, levels of Do2, Vo2DIR, and Vo2INDIR did not differ between septic and control animals, nor did they differ between septic survivors and nonsurvivors. Because levels of Vo2DIR and Vo2INDIR were similar in both groups, we pooled data from septic and control animals. Throughout the study, Vo2 showed a moderate association with Vo2INDIR (r = 0.55, p = 0.003), but mean Vo2DIR was lower at baseline (p = 0.001) and on Day 21 (p = 0.07) and greater on Day 2 (p < 0.01). In summary, our techniques, which detected small changes in both Vo2DIR and Vo2INDIR occurring with volume infusion, did not demonstrate differences in these parameters comparing control and septic animals. These results in euvolemic septic animals suggest that total body Vo2 may not reflect pathogenetic mechanisms during sepsis and septic shock. Furthermore, these results suggest that although the level of total body Vo2 may reflect the effects of therapeutic interventions such as volume loading, it should not itself serve as a therapeutic target.

Controlled trials of rG-CSF and CD11b-directed MAb during hyperoxia and E. coli pneumonia in rats.

We studied the effects of inhibiting and augmenting neutrophil function by using an immunocompetent rat model of infectious and hyperoxic lung injury. After intrabronchial Escherichia coli challenge at all fractional inspired O2 (FIO2) values studied (FIO2 = 0.21, 0.60, and 0.95) and after lethal O2 exposure alone (FIO2 = 0.90), lung injury, as measured by histological and physiological changes, was reduced by a CD11b/CD18-directed monoclonal antibody (MAb 1B6, P < 0.05 vs. controls) but was increased by recombinant granulocyte colony-stimulating factor (rG-CSF; P < 0.05 vs. control; MAb 1B6 vs. rG-CSF, P < 0.004). Pulmonary neutrophil counts were reduced by MAb 1B6 (P < 0.04) and increased by rG-CSF (P < 0.0004) compared with control animals. However, despite antibiotics, MAb 1B6 and rG-CSF both significantly increased the relative risk of death, independent of O2 concentration, during E. coli pneumonia (1.74 [symbol: see text] 1.20 and 2.39 [symbol: see text] 1.19, respectively, each P < 0.01). During lethal hyperoxia, MAb 1B6 increased the relative risk of death (1.76 [symbol: see text] 1.28, P < 0.16), whereas rG-CSF had no effect on survival (0.97 [symbol: see text] 1.28, P = 0.89). Thus inhibition of neutrophil function attenuated and enhancement worsened lung injury in response to infectious and hyperoxic challenges, supporting a pathophysiological role of the neutrophil in these processes. However, it is problematic that MAb 1B6 therapy, despite preventing lung damage, ultimately worsened host defenses and survival. Furthermore, rG-CSF also adversely affected survival during infectious lung injury, demonstrating the inherent risks of inhibiting or augmenting neutrophil function in an immunocompetent host during infection.

Cardiopulmonary effects of granulocyte colony-stimulating factor in a canine model of bacterial sepsis.

We investigated the effects of recombinant granulocyte colony-stimulating factor (G-CSF) in a canine model of septic shock. Awake 2-yr-old beagles were studied before and after intraperitoneal placement of an Escherichia coli-infected clot. Nine days before and until 3 days after clot placement, animals received daily high-dose (G-CSF (5 microgram/kg body wt; n = 17), low-dose G-CSF (0.1 microgram/kg body wt; n = 17), or a control protein (5 micrograms/kg body wt; n = 20). Survival rate was greater (P < 0.04, Wilcoxon test) in the high-dose G-CSF group (14/17) than in the low-dose G-CSF (10/17) and control (12/20) groups. High-dose G-CSF improved cardiovascular function, as evidenced by increased left ventricular ejection fraction (day 1 after clot; P < 0.001) and mean arterial pressure (day 2; P < 0.02) compared with low-dose G-CSF and control groups. High-dose G-CSF increased (P < 0.001) mean peripheral neutrophils before (-3 days) and after (2 h to 4 days) clot and produced a more rapid (P < 0.001) rise (day 2) and fall (day 4) in mean alveolar neutrophil numbers compared with the low-dose G-CSF and control groups. High-dose G-CSF decreased mean serum endotoxin (2-8 h; P < 0.002) and tumor necrosis factor (2 h; P < 0.02) levels and lowered blood bacteria counts (2-6 h; P < 0.04) compared with the low-dose G-CSF and control groups. Thus, in this canine model, G-CSF sufficient to increase peripheral neutrophils before and during peritonitis and septic shock enhances host defense, reduces cytokine (tumor necrosis factor) levels, and improves cardiovascular function and survival.