Effects of a leukotriene antagonist on the early hemodynamic manifestations of group B streptococcal sepsis in piglets

In order to evaluate the influence of leukotrienes on group B streptococcal (GBS) sepsis we studied the effect of a leukotriene antagonist, FPL 57231, on the early hemodynamic changes occurring secondary to an infusion of live GBS. Paralyzed, mechanically ventilated piglets received a continuous intravenous infusion of bacteria (5 X 10(8) org/kg/min) while systemic arterial pressure and pulmonary artery pressure were measured continuously. Cardiac output was measured by thermodilution; and plasma samples for determination of thromboxane B2 and 6-keto-PGF1 alpha were taken at preset intervals. In addition to GBS, treatment animals received a continuous infusion of FPL 57231 starting 15 min after the bacterial infusion was begun. Study animals as a whole responded to bacteria within 15 min with a marked elevation in pulmonary artery pressure from 13.6 +/- 4 to 44.6 +/- 6 mm Hg (p less than 0.001), and a decline in PaO2 (79 +/- 9 to 44 +/- 5 mm Hg) (p less than 0.001) and a cardiac output (0.27 +/- 0.07 to 0.15 +/- 0.06 liter/min/kg) (p less than 0.0001). In animals treated with FPL 57231 these changes were reversed or significantly attenuated by 60 min. In the control group pH deteriorated significantly to 7.17 +/- 0.1 compared to baseline values (p less than 0.01) by 60 min, while treatment group animals maintained a pH of 7.3 +/- 0.23. Thromboxane B2 and 6-keto PGF1 alpha were similar in both groups and did not change during the study period. In addition, survival was significantly longer in treatment (191 +/- 44 min) compared to control animals (100 +/- 32 min) (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pentoxifylline on the cardiovascular manifestations of group B streptococcal sepsis in the piglet.

Pentoxifylline (PTXF) is a methylxanthine that modifies leukocyte function and inhibits cytokine release. To evaluate its effects on the cardiovascular manifestations of sepsis secondary to group B streptococci, 14 anesthetized, mechanically ventilated piglets were studied over a 240-min period. Animals were randomly assigned to a treatment group that received a PTXF bolus (20 mg/kg) followed by a continuous infusion of 5 mg/kg/h before and during group B streptococci (1 x 10(8) colony forming units/kg/min) administration and a control group that received saline as a placebo. Comparison of the hemodynamic measurements and arterial blood gases during the first 90 min of PTXF treatment with those of the control group resulted in the following 90 min values: systemic arterial blood pressure was significantly higher in the PTXF group (89 +/- 10 versus 56 +/- 30 mm Hg; p less than 0.005) as was cardiac output (0.18 +/- 0.04 versus 0.10 +/- 0.07 L/kg/min; p less than 0.005). Pulmonary vascular resistance remained lower in the PTXF-treated animals (135 +/- 117 versus 248 +/- 119 mm Hg/L/min/kg; p less than 0.001), and these animals were less acidotic as measured by pH (7.07 +/- 0.2 versus 7.31 +/- 0.1; p less than 0.05) and base deficit (-15 +/- 9 versus -5 +/- 2 mmol/L; p less than 0.05). Median survival time was significantly longer in the PTXF group (210 versus 90 min; p less than 0.002). These data demonstrate that PTXF can ameliorate some of the deleterious hemodynamic manifestations of group B streptococci sepsis and result in improved survival in a young animal model.     

Oxygen delivery, oxygen consumption, and metabolic acidosis during group B streptococcal sepsis in piglets

The development of metabolic acidosis during neonatal sepsis with group B streptococci (GBS) has been attributed to progressive tissue ischemia resulting from reduced oxygen delivery (QO2). Using an animal model of GBS disease, we attempted to test this hypothesis by comparing the development of metabolic acidosis in two groups of piglets with comparably diminished systemic QO2, one septic and one not. Eighteen anaesthetized piglets were instrumented to observe aortic pressure, cardiac output, arterial and mixed venous blood gases, oxygen content, and hemoglobin concentration. QO2, oxygen consumption, and oxygen extraction ratio were calculated. Six piglets (group 1) received continuous infusion of live GBS organisms; six piglets (group 2) received continuous infusion of phenylephrine (PE), beginning with 10-micrograms/kg/min and increasing as required to match the PE-induced reduction in QO2 to the fall observed in the group 1 (GBS) piglets at each 30-min interval. Group 3 piglets (n = 6) received 0.9% saline and served as controls. No differences in either cardiac output or QO2 were noted comparing GBS and PE piglets at any time interval from 0-180 minutes. At 120, 150, and 180 minutes, both QO2 and cardiac output were lower in GBS and PE piglets compared to controls. Despite equivalent reductions in cardiac output and QO2, only GBS piglets developed significant metabolic acidosis, while pH and base deficit for PE piglets did not differ from controls. Oxygen consumption did not differ significantly among the three experimental groups at any observation time. Oxygen extraction ratio did not differ comparing PE and GBS piglets at any observation time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of early onset group B streptococcal sepsis in the newborn

: There is an urgent need for strategies to prevent early onset group B streptococcal sepsis in the newborn. The most effective mechanism is the identification of maternal carriers of the organism and interruption of transmission during labour. Vaginal culture is currently the most reliable method for the identification of carriers. Antibiotic prophylaxis for known carriers in labour has been demonstrated to be effective as standard management practice in a number of Australian institutions and is the best available strategy at this stage.     

Significance of placental findings in early-onset group B streptococcal neonatal sepsis

Assessment of placental pathology and its relationship to historical data, initial laboratory parameters, and outcome was undertaken in 22 cases of early-onset group B streptococcal sepsis of the neonate. Fourteen (64%) of the placentas demonstrated chorioamnionitis, six (27%) funisitis, and in nine (41%) gram stain demonstrated organisms within the membranes. Focal villous edema was observed in five (23%) cases and diffuse villous edema in four (18%). No placenta demonstrated chorangiosis. Placental inflammation was significantly (p less than 0.05) associated with prematurity, prolonged rupture of membranes, and onset of symptoms at less than 3 hours of age. No placental change was significantly associated with outcome or with neutropenia, which was the only parameter assessed that appeared to have prognostic value.     

Newborn sepsis following antepartum group B streptococcal maternal infection in rats

Group B streptococcus is an important pathogen in man and infection due to this bacteria is responsible for significant mortality and morbidity in neonates. An animal model of neonatal infection caused by group B streptococcus that results from vertical transmission is described. Nine pregnant Sprague-Dawley rats received intraperitoneal inoculation of 10(9)-10(10) colony forming units of group B streptococcus on day 20 or 21 of gestation. Four of nine rats died following inoculation. A total of 51 pups was born to the surviving five mothers. Pups were sacrificed at 4- to 8-h intervals and cultures of blood, brain, liver, and spleen were obtained. Nineteen of 51 pups (37%) had group B streptococcus isolated from blood or tissues within the first 48 h of life. Results suggest that antepartum systemic infection in rats can result in vertical transmission of disease. This animal model can be used to further study the mechanisms of transmission of group B streptococcus and the pathogenesis and treatment of neonatal sepsis caused by this pathogen.     

The effect of hybridoma antibody administration upon neutrophil kinetics during experimental type III group B streptococcal sepsis

Groups of newborn rats were transthoracically inoculated with 1 X 10(6) type III group B streptococci/g body wt, either alone or in combination with 1.5 microgram/g body wt of type-specific antibody derived from hybridoma cell lines. Ninety-four percent of the animals who received bacteria alone died. In contrast, none of those treated with antibody died (P less than 0.005). Kinetic studies suggested that antibody may have offered protection, In part, by facilitating the neutrophil response. Animals who received only bacteria exhibited a marked neutropenia (20 +/- 18/mm3, mean +/- S.E.M.) whereas infected animals treated with antibody did not (3800 +/- 30/mm3, P less than 0.001). Furthermore, within 2 h of inoculation, antibody-treated animals mobilized and stored neutrophils, whereas significant neutrophil mobilization did not occur in the animals which received bacteria alone until 6 h. In the animals receiving bacteria alone, exhaustion of the neutrophil supply quickly occurred (remaining storage neutrophils at 6 h, 0.2 +/- 0.1 X 10(6) cells). In contrast, animals, which received antibody, maintained an adequate supply of stored neutrophils (7.0 +/- 0.4 X 10(6) P less than 0.001). The migration of neutrophils to the site of inoculation was measured by assaying the lungs' content of myeloperoxidase, a marker enzyme for granulocytes. The right and left lungs of animals not receiving antibody accumulated the same quantity of neutrophils, with peak pulmonary neutrophil accumulation occurring 6 h after the infection. In antibody recipients, however, the inoculated lung accumulated significantly more neutrophils than the opposite lung and peak pulmonary neutrophil accumulation occurred at 2 rather than 6 h.     

新生儿B族链球菌败血症33例临床分析

目的：探讨新生儿B族链球菌(group B streptococcus,GBS)败血症的临床特点。方法收集2011年3月至2014年10月泉州市儿童医院NICU收治的GBS败血症患儿的资料,回顾性分析GB S败血症患儿的围产因素、临床表现、实验室检查、治疗与转归。结果 GB S 败血症33例,占住院患儿的2.0‰(33/16448)。其中早发型败血症21例,均为足月儿,呼吸窘迫13例、气促11例、青紫10例。晚发型败血症12例,足月儿8例,早产儿4例,以高热为首发症状入院10例,6例合并化脓性脑膜炎。33例血GB S阳性标本均对万古霉素敏感,青霉素联合美罗培南治疗有效,其中18例治愈出院,临床好转后自动出院9例,死亡2例,放弃治疗死亡4例,总病死率18.2%。结论新生儿GB S败血症临床症状明显,早发型病例以呼吸系统症状为主,晚发型病例以高热为首发症状。母孕后期应常规筛查,重视新生儿早期临床表现,尽早行病原学检测,合理足疗程使用敏感抗生素治疗。     

新生儿晚发型B族链球菌败血症临床特征及预后分析

目的探讨晚发型B族链球菌（GBS）败血症的临床特征及预后情况。方法回顾性分析新生儿重症监护室（NICU）2007年1月-2011年12月出院诊断晚发型GBS败血症的15例新生儿以及同期出院诊断为晚发型非GBS革兰阳性菌败血症34例新生儿的临床资料。结果晚发型GBS败血症与晚发型非GBS革兰阳性菌败血症新生儿在气促、抽搐和呼吸暂停等临床表现方面,差异有统计学意义（P均<0.05）。晚发型GBS败血症组脑脊液白细胞计数>100×106/L、超敏C反应蛋白>100 mg/L及脑脊液葡萄糖<3.11 mmol/L的比例高于非GBS革兰阳性菌败血症组（P<0.05）。GBS对青霉素、氨苄青霉素、头孢曲松、哌拉西林/他唑巴坦、左氧氟沙星、万古霉素敏感,对红霉素及庆大霉素耐药率均为87.5%。晚发型GBS败血症与非GBS革兰阳性菌败血症患儿在并发脑膜炎及脑积水、脑室管炎等后遗症的差异也有统计学意义（P<0.05）,但病死率的差异无统计学意义（P>0.05）。结论晚发型GBS败血症起病较隐匿,症状不典型,并发症多,且易有后遗症;对可疑GBS败血症新生儿应早期使用有效抗生素治疗。     

Group B streptococcal sepsis in piglets: effect of combined pentoxifylline and indomethacin pretreatment.

Group B streptococcus (GBS), a common neonatal gram-positive pathogen, causes similar pathophysiology in human newborns and neonatal animal models of sepsis. Animal models of GBS sepsis demonstrate a two-phase response: 1) an acute phase (less than 1 h) of increased pulmonary artery pressure (Ppa) and reduced arterial oxygen pressure (PaO2) that is associated with increased serum thromboxane B2 (TxB2) and 2) a late phase (2-4 h) of persistently increased Ppa and reduced PaO2, reduced systemic arterial pressure, and progressive fall in cardiac output that is associated with increased serum TxB2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and tumor necrosis factor-alpha (TNF alpha). We hypothesized that pretreatment of piglets with both pentoxifylline (PTF), an inhibitor of TNF alpha production and activity, and indomethacin (INDO) would 1) inhibit GBS-induced TxB2, 6-keto-PGF1 alpha, and TNF alpha and 2) prevent both the acute- and late-phase physiologic responses of GBS sepsis. Combined PTF and INDO pretreatment of anesthetized, mechanically ventilated piglets infused with GBS (1.25 x 10(9) colony forming units/kg/h) for 4 h prevented GBS-induced increases in Ppa at 1 h (GBS + PTF + INDO: 1.8 +/- 0.07 kPa versus GBS alone: 4.7 +/- 0.1 kPa) and markedly attenuated increases in Ppa at 4 h (GBS + PTF + INDO: 2.1 +/- 0.1 kPa versus GBS alone: 4.4 +/- 0.1 kPa).(ABSTRACT TRUNCATED AT 250 WORDS)     

Early-onset group B streptococcal sepsis in a preterm infant with Kostmann syndrome

A preterm infant died of group B streptococcal sepsis 7 h after birth. The infant's complete blood count showed total agranulocytosis. Histopathology of the major organs showed significant bacterial invasion without infiltration of polymorphonuclear leucocytes. Examination of the bone marrow revealed normal cellularity of the granulocyte precursors with arrested maturation. These findings are consistent with Kostmann syndrome. CONCLUSION: It is suggested that in patients with deteriorating early-onset infection, underlying congenital abnormalities in host defence, such as Kostmann syndrome, should be considered.     

Treatment of experimental group B streptococcal infection with hybridoma antibody

Previous studies have shown a reduction in mortality rate from 90% to zero when neonatal rats, inoculated with group B streptococci (GBS) were injected with type-specific IgM antibody. However, in those studies, the antibody was administered simultaneously with the bacteria and at the same site, unlike the situation which would exist if antibody was used clinically to treat established infection. In the present experiments, we administered antibody intraperitoneally at various intervals following intrathoracic inoculation of GBS. When antibody was administered immediately after, or up to 2 h following bacterial inoculation, all animals survived. When antibody administration was delayed for 4, 5, or 6 h, survival rates of 92, 60, and 29% were observed. When antibody administration was delayed for more than 6 h, no survival occurred. Failure of antibody to protect animals from death coincided temporally with profound depletion of the neutrophil storage pool. In other experiments, depletion of the neutrophil storage pool was produced by a separate, noninfectious mechanism (subcutaneous implantation of sterile polyvinyl sponge discs) after which animals were inoculated with GBS. Antibody did not provide protection from death in animals with neutrophil storage pool depletion.     

Neonatal group B streptococcal sepsis: effects of late treatment with dazmegrel

Neonatal group B streptococcal (GBS) sepsis produces pulmonary arterial hypertension and hypoxemia that are preventable by pretreatment with the selective thromboxane A2 synthase inhibitor, dazmegrel. In the present experiment we administered dazmegrel (8 mg/kg) 2 h after the initiation of a 2 1/2 h infusion of 5 X 10(8) GBS/kg/h in ten 2- to 3-wk-old piglets. The multiple inert gas elimination technique was used to measure intrapulmonary shunt and alveolar ventilation to pulmonary perfusion mismatching. Thromboxane B2, the stable metabolite of thromboxane A2, and 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin, were assayed in arterial blood. Pulmonary arterial pressure increased immediately after initiation of the GBS infusion, rising from 12 +/- 2 to 34 +/- 4 torr (p less than 0.02); pulmonary vascular resistance increased by 400% (p less than 0.01). Arterial hypoxemia developed (p less than 0.02) in association with an increase in the low ventilation-perfusion ratio index but without a significant increase in intrapulmonary shunt. Thromboxane B2 levels increased 10-fold. Infusion of the carrier substance for dazmegrel after 2 h of GBS infusion produced no change in any variables. In contrast, infusion of the drug resulted in the return to pre-GBS infusion baseline values for both pulmonary arterial pressure and pulmonary vascular resistance. However, no improvement in arterial pO2 or in the low ventilation-perfusion ratio index occurred. Both pulmonary vascular resistance and pulmonary arterial pressure remained normal for 0.5 h after dazmegrel administration despite continued GBS infusion. Thromboxane B2 levels were decreased 30 min after dazmegrel (p less than 0.02), but remained greater than pre-GBS levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Granulocytic stem cell (CFUc) proliferation in experimental group B streptococcal sepsis

Adult rats infected with group B streptococci (GBS) develop neutrophilia and display a marked increase in granulocytic stem cells (CFUc). In contrast, infected neonatal rats develop a profound neutropenia and their CFUc do not increase. In order to better understand this phenomenon, we assessed the CFUc proliferative rate in control and infected adult and neonatal rats using the technique of [3H]-thymidine suicide. Beginning only 3 h after GBS inoculation, adult rats increased CFUc proliferative activity, as illustrated by an increase in thymidine suicide, from 38 +/- 2% cell kill in control animals to 70 +/- 2% when infected (mean + S.E., P less than 0.001). In contrast, the CFUc thymidine suicide rate did not increase in infected neonates. It was noted, however, that the baseline CFUc thymidine suicide rate in uninfected neonatal rats exceeded the rate in uninfected adult rats by 2-3-fold. The CFUc thymidine suicide rate was therefore determined in uninfected premature (74 +/- 1%), newborn (70 +/- 2%), 1-wk-old (70 +/- 1%), 6-wk-old (32 +/- 1%) and 6-month-old (37 +/- 3%) rats. These findings suggest that the proliferative rate of granulocytic stem cells is already maximal or near maximal in noninfected neonatal animals. In contrast to adults, the neonates' granulocyte production from stem cells can not significantly increase, even if bacterial infection is present.