Prevention of catheter thrombosis increases survival,but does not modify lung injury in rats receiving long-term parenteral nutrition

It has previously been shown that rats receiving total parenteral nutrition (TPN) or each component of TPN die within 40 days of treatment. Central catheter thrombosis and lung injury were constant findings. The aim of the present study was to examine the impact of central thrombosis on lung injury and survival in rats receiving long-term parenteral nutrition. In the first part of the study TPN was infused via the jugular vein and incidence of central venous thrombosis and rate of survival were recorded. Addition of low molecular weight heparin (LMWH) reduced central thrombosis from 6 out of 7 animals to 2 out of 7 animals (p=0.027) and increased survival from 17.1±4.5 days to 32.4±4.9 days (p=0.04). In the second part of the study four infusion groups were established. Group 1 (controls) received saline 100?mL/kg/day via the jugular vein (n=6). Group 2 received Intralipid&;lt;formula&;gt;^®&;lt;/formula&;gt; 40?mL/kg/day via the jugular vein (n=7). Group 3 received Intralipid 40?mL/kg/day via the portal vein (n=7). Group 4 received Intralipid 40?mL/kg/day with added LMWH 70?U/kg/day (n=7). Lung injury and occurrence of central thrombosis were investigated. Lung injury was assessed by measuring pulmonary arterial pressure (Ppa), clearance of serotonin by the vascular endothelium and the capillary filtration coefficient (CFC). Either infusion via the portal vein or the addition of LMWH to the infusion via the jugular vein prevented central thrombus formation, but the lung injury was not modified by this method compared with infusing Intralipid via the jugular vein without LMWH. In conclusion, central thrombus formation contributes to death in rats receiving parenteral nutrition. The mechanism of the injurious effect of central thrombosis remains unknown, but central thrombus formation seems not to increase lung injury caused by Intralipid.     

Mild or moderate hypothermia, but not increased oxygen breathing, increases long-term survival after uncontrolled hemorrhagic shock in rats

OBJECTIVE: To test the hypotheses that, for uncontrolled hemorrhagic shock (UHS) in rats, mild hypothermia, compared with normothermia, would increase long-term survival as well as moderate hypothermia, oxygen breathing would increase survival further, and hypothermia and oxygen would mitigate visceral ischemia (dysoxia) during UHS. DESIGN: Prospective, randomized study. SETTING: Animal research laboratory. SUBJECTS: A total of 54 male Sprague-Dawley rats. INTERVENTIONS: Under light anesthesia and spontaneous breathing, rats underwent UHS phase I of 75 mins, with initial withdrawal of 3 mL/100 g of blood over 15 mins, followed by UHS via tail amputation and limited fluid resuscitation to maintain mean arterial pressure at > or =40 mm Hg; resuscitation phase II of 60 mins (from 75 mins to 135 mins) with hemostasis and aggressive fluid resuscitation to normalize hemodynamics; and observation phase III to 72 hrs. Rats were randomly divided into nine groups (n = 6 each) with three rectal temperature levels (38 degrees C [normothermia] vs. 34 degrees C [mild hypothermia] vs. 30 degrees C [moderate hypothermia]) by surface cooling; each with 3 FIO2 levels (0.25 vs. 0.5 vs. 1.0). MEASUREMENTS AND MAIN RESULTS: Hypothermia increased blood pressure compared with normothermia. Increased FIO2 had no effect on blood pressure. Additional blood loss from the tail cut was small, with no differences among groups. Hypothermia and FIO2 of 0.5 decreased visceral hypoxia, as measured by the difference between visceral (liver and jejunum) surface Pco2 and PaCO2 during UHS. Compared with normothermia, mild hypothermia increased the survival time and rate as well as moderate hypothermia (p < .01 by life table), without a significant difference between mild and moderate hypothermia. Increased FIO2 had no effect on survival time or rate. CONCLUSIONS: After severe UHS and resuscitation in rats, mild hypothermia during UHS, compared with normothermia, increases blood pressure, survival time and 72-hr survival rate as well as moderate hypothermia. Mild hypothermia is clinically more feasible and safer than moderate hypothermia. Increased FIO2 seems to have no significant effect on outcome.     

Pulmonary function in rats dying from long-term parenteral nutrition

Infusion of Vamin or Intralipid causes death in a rat model of continuous parenteral nutrition. Morphological investigations have shown vascular injury and thrombus formation in the lungs. In this study, lung function in rats was examined before death due to parenteral nutrition. The rats were fed saline intravenously (group I); 100 mL kg(-1) day(-1) (controls); a 7% amino acid-glucose solution (Vamin-Glukos) (group II); 100 mL kg(-1) day(-1), or 20% fat emulsion (Intralipid) (group III); 40 mL kg(-1) day(-1). The infusion was stopped when the condition of the rats deteriorated. In a saline-perfused, isolated lung model, pulmonary arterial pressure (Ppa), transpulmonary pressure (Ptp), endothelial function, measured as inactivation of serotonin (bioassay), and the capillary filtration coefficient (CFC) were determined. Haematological parameters were also evaluated. Constant findings in group II and III were central thrombus formation, anaemia and thrombocytopenia. Ppa increased from 0.7 (0.04) kPa in group I to 1.4 (0.1) kPa and 1.7 (0.1) kPa in groups II and III, respectively (p<0.001). Inactivation of serotonin was reduced to 36% (2) in group II and 37% (2) in group III compared with 74% (5) in group I (p<0.002). CFC increased to 25 mg min(-1) (5) (group II) and 30 mg min(-1) (6) (group III) compared with 13 mg min(-1) (2) in controls (p=0.01). The study shows that major pulmonary hypertension and severe reduction of the endothelial function are present when rats deteriorate after infusion of parenteral nutrition substrates.     

经外周静脉植人卷尺导管进行肠外营养的效果观察

目的探讨卷尺导管在肠外营养中应用的效果。方法对46例胃肠癌术后患者采用卷尺导管(外周静脉穿刺植入)肠外营养,并与44例胃肠癌术后患者采用套管针肠外营养进行比较,观察两组静脉炎和渗漏的发生率。结果两组患者静脉炎和渗漏性损伤的发生率经字2检验,分别为字2=8.997,字2=14.475,P均<0.01,有显著性差异。结论卷尺导管有效地减少了肠外营养期间静脉炎和渗漏性损伤的发生;选择好血管是置管成功的保证,严格无菌操作和正压封管是预防导管性感染和导管堵塞的关键。     

Failings in the care of patients receiving parenteral nutrition

John Tingle discusses an NCEPOD report which reveals serious failings in the care of hospital patients receiving parenteral nutrition.     

Deferoxamine injection does not affect bleomycin-induced lung fibrosis in rats

Bleomycin is an antineoplastic agent that causes a dose-related lung fibrosis that limits its therapeutic effectiveness. It has been proposed that the cellular toxicity and antitumor effects of bleomycin occur by formation of O2-Fe(II)-bleomycin complexes that degrade DNA and release O2- and OH radicals that attack other cellular components. Twice daily injections of the iron chelator deferoxamine were utilized in an attempt to ameliorate bleomycin-induced lung fibrosis. They failed to diminish bleomycin-induced lung inflammation and fibrosis in rats.     

Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model

Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B₄ and leukotriene B₅ secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B₅, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids.     

Effect of growth hormone on muscle and liver protein synthesis in septic rats receiving glutamine-enriched parenteral nutrition

OBJECTIVE: Administration of recombinant human growth hormone (rhGH) to critically ill adults in an attempt to attenuate catabolism was associated with increased morbidity and mortality. Possible explanations included inhibition of glutamine release from skeletal muscle and consequent restriction of splanchnic glutamine supply. In this study, we examined the effects of rhGH on plasma glutamine levels and on muscle and liver glutamine concentrations and protein synthesis rates in sepsis. We investigated the possibility that administration of supplemental glutamine might ameliorate any adverse effects of rhGH. DESIGN: Prospective study in rats rendered septic by cecal ligation and puncture. SETTING: University hospital laboratory. SUBJECTS: A total of 78 male Wistar rats in six groups. INTERVENTIONS: Animals received 6-hr tail vein infusions, commencing 18 hrs after cecal ligation and puncture, of either (a) 0.9% sodium chloride, (b) a standard parenteral nutrition (PN) solution without glutamine, or (c) an isocaloric, isonitrogenous PN solution with glutamine. PN groups received 400 microg rhGH or equivolume 0.9% sodium chloride vehicle in a divided subcutaneous and intravenous dose at PN commencement. Sacrifice was at the end of the infusion period. A further group was unoperated and uninfused and killed at 24 hrs as baseline controls. MEASUREMENTS AND MAIN RESULTS: Glutamine concentrations were measured by fluorometry. Protein synthesis in muscle and liver was measured by a "flooding-dose" technique employing L-[4-H]phenylalanine. Plasma glutamine was increased after cecal ligation and puncture except in the saline and glutamine with rhGH animals. Muscle glutamine was reduced after cecal ligation and puncture and was significantly lower in animals receiving standard PN with rhGH vs. saline alone. Liver glutamine was increased in animals receiving saline and those receiving standard PN with rhGH. PN, with or without glutamine, increased muscle protein synthesis, and the administration of rhGH tended to further increase this effect. Neither PN, glutamine, nor rhGH had an effect on the increased liver protein synthesis characteristic of sepsis. CONCLUSIONS: In sepsis, increased muscle protein synthesis with PN and rhGH administration is not associated with increased muscle glutamine levels. Administration of rhGH does not result in reduced liver glutamine levels or rates of hepatic protein synthesis. PN containing glutamine was no more efficacious than standard PN at increasing muscle protein synthesis.     

Body position does not influence the location of ventilator-induced lung injury

OBJECTIVE: To ascertain whether the locations of ventilator-induced lung injury (VILI) are influenced by body position. DESIGN: Randomized prospective short-term study. SETTING: Animal laboratory at a university school of medicine. INTERVENTIONS: Twelve white rabbits were mechanically ventilated in IMV mode with an infant ventilator (V.I.P. Bird, Bird Products, Palm Springs, Calif., USA). Based on the results of a preliminary study to determine the ventilator settings at which the lungs of rabbits were injured within 5 h in the supine position, the ventilator was set at F(I)O2 0.21, at a rate of 30/min, T(I) 0.6 s, peak inspiratory pressure 30 cm H2O, inspiratory flow 10 l/min with no applied positive end-expiratory pressure (PEEP). Six of the animals were tested in the supine position and the other six in the prone position. Respiratory gases were measured and CT scanning was performed every 30 min. The animals were ventilated for 5 h or until pulmonary parenchymal opacification was detected. The lungs were divided into three areas from apex to base and three levels from ventral to dorsal, and the location of opacification was ascribed according to this scheme. After the experiment, the lungs were excised and examined histologically. MEASUREMENTS AND RESULTS: Parenchymal opacification occurred mainly in the dorsal lung areas. The time from the beginning of ventilation to the appearance of lung damage was 60-120 min in the supine (S) group, and 60-270 min in the prone (P) group, and it was significantly longer in the prone group (P < 0.01). We observed diffuse lung damage, including hyaline membrane formation, intra-alveolar edema, and infiltration of inflammatory cells. CONCLUSIONS: Body position affected the time course of the development of VILI, but it did not affect the location.     

Sepsis-induced lung injury in rats increases alveolar epithelial vulnerability to stretch

OBJECTIVE: Previous in vitro models have shown that cellular deformation causes dose-dependent injury and death in healthy rat alveolar epithelial cells (AECs). We compared the viability of AECs from septic rats with those from nonseptic rats after 1 hr of cyclic equibiaxial stretch. We hypothesized that sepsis would increase stretch-induced cell death. DESIGN: Laboratory investigation. SETTING: University research laboratory. SUBJECTS: Thirty-seven male Sprague-Dawley rats weighing 240-260 g. INTERVENTIONS: Anesthetized rats were subjected to cecal ligation and double puncture (2CLP) or sham laparotomy without cecal ligation or puncture (sham). After 24 or 48 hrs, AECs were isolated, seeded in custom wells, and maintained in culture for 48 hrs before study. AECs were stretched cyclically (15/min) to a 0%, 12%, 25%, or 37% change in surface area (DeltaSA) for 1 hr. Cell viability, phenotypic markers, and nuclear factor-kappaB intracellular localization were assessed using fluorescent immunocytochemistry. MEASUREMENTS AND MAIN RESULTS: Phase and fluorescent images were evaluated for all studies. Response to stretch was the same at 24 and 48 hrs after 2CLP. Relative to sham, 2CLP significantly increased cell death at 25 and 37% DeltaSA (p<.003, analysis of variance). Relative to sham, 2CLP did not alter expression of type I or type II phenotypic markers. Nuclear factor-kappaB within the nuclear compartment was observed after 2CLP in unstretched cells and after 1 hr of cyclic stretch at 37% DeltaSA. In sham, nuclear factor-kappaB within the nuclear compartment was seen only after stretch. CONCLUSIONS: AECs isolated from septic rats are more vulnerable to mechanical deformation injury than AECs from nonseptic animals.     

Low positive end-expiratory pressure does not exacerbate nebulized-acid lung injury in dogs

It is not clear if low end-expiratory pressures contribute to ventilator-induced lung injury in large animals. We sought to determine whether ventilation with a low level of positive end-expiratory pressure (PEEP) worsens preexisting permeability lung injury in dogs. Lung injury was initiated in 20 mongrel dogs by ventilating with nebulized 3N hydrochloric acid until a lower inflection point (LIP) appeared on the respiratory system pressure-volume loop. One group of 10 dogs was then ventilated for 4 hours with PEEP set below the LIP (low PEEP), whereas the remaining group of dogs was ventilated for the same time period with similar tidal volumes but with PEEP set above the LIP (high PEEP). We found histologic evidence of reduced alveolar volumes in the low-PEEP animals. However, there were no differences in neutrophil infiltration, lung lobe weights, pulmonary capillary hemorrhage or congestion, or arterial endothelin-1 concentration between the 2 protocol groups. In conclusion, we were unable to demonstrate that ventilation with PEEP set below the LIP exacerbates hydrochloric acid-induced lung injury in dogs.     

Intraperitoneal, but not enteric, adenosine administration improves survival after volume-controlled hemorrhagic shock in rats

OBJECTIVE: To circumvent the potential adverse systemic side effects of adenosine, this study explored the potential benefit of intraperitoneal or enteric adenosine on survival and inflammatory responses after volume-controlled hemorrhagic shock. DESIGN: Prospective, randomized, and blinded. A three-phase, volume-controlled hemorrhagic shock model was used: hemorrhagic shock phase (120 mins), resuscitation phase (60 mins), and observation phase (72 hrs). Three groups were compared: controls, intraperitoneal adenosine, and enteric adenosine. SETTING: Animal research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Starting at 20 mins of hemorrhagic shock and continuing through the resuscitation phase, all three groups received both intraperitoneal lavage and repeated bolus injections into the ileum of vehicle (normal saline) or adenosine. In the intraperitoneal adenosine group (n = 10), adenosine solution (0.1 mM) was used for intraperitoneal lavage. In the enteric adenosine group (n = 10), adenosine (1.0 mM) was injected into the ileum. Blood cytokine concentrations and leukocyte infiltration in lungs and liver were studied in 12 separate rats (control and intraperitoneal adenosine, n = 6 each) with the same hemorrhagic shock model at resuscitation time 1 hr or 4 hrs. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and heart rate were similar between the three groups during hemorrhagic shock and resuscitation. Potassium, lactate, and blood urea nitrogen concentrations were lower and arterial pH was higher in the intraperitoneal and enteric adenosine groups compared with the control group (both p <.05). Survival time to 72 hrs was longer in the intraperitoneal adenosine group than in the control group(p <.05). Neither plasma interleukin-1beta, interleukin-6, interleukin-10, and tumor necrosis factor-alpha concentrations nor leukocyte infiltration in the lungs and liver was different between the control and intraperitoneal adenosine groups. CONCLUSIONS: The administration of adenosine via the intraperitoneal route improves survival time after severe volume-controlled hemorrhagic shock in rats without worsening hypotension or bradycardia. This beneficial effect may not be attributable to effects of adenosine on the inflammatory response.     

Pressure-limited ventilation with permissive hypercapnia and minimum PEEP in salinelavaged rabbits allows progressive improvement in oxygenation,but does not avoid ventilator-induced lung injury

Objective To determine whether pressure-limited intermittent mandatory ventilation with permissive hypercapnia and positive end-expiratory pressure (PEEP) titrated to arterial oxygen tension (PaO₂) prevents or reduces acute lung injury, compared to conventional ventilation, in salinelavaged rabbits.Design Prospective randomised trial.Setting University animal laboratory.Subjects 18 New Zealand White rabbits.Interventions Following five sequential saline lung lavages, anaesthetised rabbits were randomly allocated in pairs to receive either of two ventilation protocols using intermittent mandatory ventilation. The study group had peak inspiratory pressure limited to 15 cm H₂O and arterial partial pressure of carbon dioxide (PaCO₂) was allowed to rise. The control group received 12 ml/kg tidal volume with rate adjusted for normocarbia. PEEP and fractional inspired oxygen (FIO₂) were adjusted to maintain PaO₂ between 8 and 13.3 kPa (60 and 100 mm Hg) using a predetermined protocol. At 10 h or following death, lung lavage was repeated and lung histology evaluated.Measurements and main results The mean increase in lavage cell counts and protein concentration and hyaline membrane scores were not significantly different between the groups. Oxygenation progressively improved more in the study group (p=0.01 vs control for PaO₂/FIO₂ ratio and alveolar-arterial oxygen tension gradient (AaDO₂)). PEEP was similar and the mean airway pressure higher in the control group, suggesting that this probably resulted from less ventilatorinduced injury in the study group. Four deaths occurred in the control group (three due to pneumothorax and one to hypoxaemia) and none in the study group (p=0.08).Conclusions This ventilatory protocol may have failed to prevent lung overdistension or it may have provided insufficient PEEP to prevent injury in this model; PEEP greater than the lower inflection point of the pressure-volume curve has been shown to prevent injury almost entirely.Funded by New Zealand Lottery Grants Board and Allen and Hanburys (NZ) Ltd.     

Haloperidol, but not olanzapine, impairs cognitive performance after traumatic brain injury in rats

OBJECTIVE: Traumatic brain injury can cause a variety of impairments, including persistent alterations in personality, mood, and cognition. Antipsychotic agents are frequently used to treat pathologic behaviors in traumatic brain injury patients, but the influence of prolonged administration of such drugs on cognition after injury is unknown. The effects of two antipsychotic drugs on cognitive recovery after traumatic brain injury were assessed using the fluid percussion model in rats. DESIGN: The typical antipsychotic, haloperidol, and the third-generation antipsychotic, olanzapine, were administered via intraperitoneal injection beginning 24 hr after injury and continuing daily for the duration of the study. Morris water maze performance was assessed on days 11-15 postinjury. RESULTS: Haloperidol, an antagonist acting on D2-like dopamine receptors, exacerbated the cognitive deficits induced by injury, as injured rats treated with 0.30 mg/kg haloperidol performed worse in the Morris water maze than injured rats treated with vehicle. CONCLUSIONS: Our results demonstrate the importance of the D2 receptor in cognitive recovery after traumatic brain injury. Also, the data illustrate that some classes of antipsychotic drugs may influence cognitive recovery, and further research is needed to determine the optimal pharmacologic treatment of aggression, agitation, and other pathologic behaviors in patients with traumatic brain injury.