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This case report describes rapid and persistent improvement after one single dose of porcine surfactant (Curosurf) 0.5 ml/kg(-1) (40 mg/kg) intratracheally for adult respiratory distress syndrome (ARDS) with severe oxygenation failure 8 h after freshwater near-drowning in a 12-year-old girl.
To evaluate the role of tumor necrosis factor (TNF)-alpha in the pathogenesis of ventilator-induced lung injury, we 1) measured TNF-alpha production in the lung caused by conventional mechanical ventilation (CMV) and 2) evaluated the protective effect of anti-TNF-alpha antibody (Ab) in saline-lavaged rabbit lungs. After they received saline lung lavage, rabbits were intratracheally instilled with 1 mg/kg of polyclonal anti-TNF-alpha Ab in the high-dose group (n = 6), 0.2 mg/kg of anti-TNF-alpha Ab in the low-dose group (n = 6), serum IgG fraction in the Ab control group (n = 6), and saline in the saline control group (n = 7). Animals then underwent CMV for 4 h. Levels of TNF-alpha in lung lavage fluid were significantly higher after CMV than before in both control groups. Pretreatment with intratracheal instillation of high and low doses of anti-TNF-alpha Ab improved oxygenation and respiratory compliance, reduced the infiltration of leukocytes, and ameliorated pathological findings. CMV led to TNF-alpha production in the lungs, and intratracheal instillation of anti-TNF-alpha Ab attenuated CMV-induced lung injury in this model.
Although several methods have been used to deliver fluid into the distal airspaces of the lung, the efficiency of these methods has been variable. Therefore, the authors have modified prior techniques to design a better method for direct visual instillation (DVI) of fluid into the trachea and compared its efficiency with two commonly used methods: nasal inhalation and invasive intratracheal instillation (delivery of the instillate by needle puncture of the trachea). The results showed that this method (DVI) can deliver fluid efficiently into either both lungs or into a single lung. Using an 131I-albumin labeling technique, DVI resulted in 92 +/- 1% retention of the labeled albumin in the lungs 1 hour after instillation, significantly greater than nasal inhalation (48 +/- 3%, P < .01) and invasive intratracheal instillation (77 +/- 3%, P < .05). Also, when bacteria (Escherichia coli) were instilled with the DVI method, the severity of gram-negative pneumonia was greater (6.5 +/- 0.5 g water/g dry weight) compared to delivery by nasal inhalation (5.5 +/- 0.4 g water/g dry weight, P < .05) or by invasive intratracheal instillation (5.9 +/- 0.4g water/g dry weight, P < .05). The authors conclude that DVI is more efficient than nasal inhalation and invasive intratracheal instillation for delivering experimental fluids into the distal airspaces of anesthetized mice. This method should be valuable for experimental lung studies in mice.
The authors constructed a D-shaped tracheal model with an elastic posterior wall, thus simulating normal tracheal anatomy more closely than previous models. The performance of 9-10 tracheal tube cuffs, of 2-3 different tube sizes (7.0-10.0 mm, ID), from six different manufacturers were tested in the model. Cuff residual volumes ranged from 1.78 to 27.35 ml. Cuff pressure and lateral wall pressures exerted by the cuff on the model were measured at the time a seal was achieved which just prevented leakage of water past the cuff. When a seal was achieved with a volume of air in the cuff less than cuff residual volume, wall pressure tended to be low (less than 35 torr) and cuff pressure closely approximated wall pressure. There was no relationship between cuff brands in the wall pressure required to effect a seal in the model. The authors conclude that intratracheal tubes should have cuffs with large residual volumes. This would permit some latitude in tube size selection while ensuring that a seal could be achieved before the cuff is inflated to its residual volume.
OBJECTIVE: To determine whether intratracheal pulmonary ventilation (ITPV) allows for effective oxygenation and ventilation at lower mean airway pressures and peak inspiratory pressures than conventional ventilation in a piglet model of meconium aspiration syndrome. DESIGN: Prospective, interventional study. SETTING: The animal research laboratory at Children's National Medical Center, Washington, DC. SUBJECTS: Twenty newborn piglets, 2 to 7 days of age, weighing 1.8 to 2.8 kg. INTERVENTION: Animals were anesthetized, paralyzed, intubated, and ventilated. Femoral arterial and venous catheters were inserted; 5 mL/kg of 20% meconium in normal saline was instilled into the endotracheal tube. Animals were randomized to either ITPV or conventional ventilation, and settings were adjusted to maintain ideal blood gases, i.e., pH 7.35 to 7.45, PCO2 40 to 45 torr (5.3 to 6 kPa), PO2 80 to 100 torr (10.7 to 13.3 kPa), and SaO2 > or = 90%. Ventilatory settings were adjusted as needed to a maximum of: FIO2 1.0, peak inspiratory pressure 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and respiratory rate 80 breaths/min. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were taken every 30 mins for 4 hrs and ventilatory settings were adjusted to maintain optimal blood gases. Heart rate, mean arterial blood pressure, and arterial saturation were monitored continuously. The animals in the ITPV group had significantly lower peak inspiratory pressure at 1, 2, 3, and 4 hrs after meconium instillation (p < .018) and significantly lower mean airway pressure at 2, 3, and 4 hrs after meconium instillation (p < .03). The mean peak inspiratory pressure in the ITPV animals ranged from 17 +/- 2.7 cm H2O at baseline to 16.6 +/- 5.7 cm H2O at 4 hrs compared with 16.5 +/- 2.7 cm H2O at baseline to 31.8 +/- 9.1 cm H2O at 4 hrs in the conventionally ventilated animals (p < .04). The mean airway pressure ranged from 6.3 +/- 1.1 mm Hg at baseline to 6.8 +/- 2.5 mm Hg at 4 hrs in the ITPV group compared with 5.5 +/- 1.2 mm Hg at baseline to 10.7 +/- 3.4 mm Hg at 4 hrs in the conventional ventilation group (p < .03). The lungs of the ITPV animals were less hemorrhagic and had less pathologic evidence of injury than the lungs of the conventionally ventilated animals. CONCLUSIONS: These results indicate that ITPV can be used to effectively ventilate and oxygenate piglets with meconium aspiration syndrome at lower mean airway pressures and peak inspiratory pressures than conventional ventilation. This lower pressure causes less injury to the lungs of the animals.
PURPOSE: Non drug loaded lipid vesicles have been investigated as promoters of pulmonary insulin absorption. METHODS: Physical mixtures of liposomes with insulin were delivered intratracheally to rats by direct instillation method at an insulin dose level of 1 U/kg. RESULTS: The overall hypoglycemic response, represented by area above the curve (AAC), correlated linearly with the lipid concentration for both the neutral and charged liposome-insulin preparations. The strongest response was observed with the positively charged liposomes followed by negatively charged and neutral liposome-insulin mixtures. Further toxicological studies indicated that charge-inducing agents, i.e., stearylamine and dicetylphosphate, can cause apparent disruption of pulmonary epithelial cells. From the difference of overall hypoglycemic response (AAC) among various formulations, it appears that the stronger hypoglycemic effect following positively charged liposome-insulin mixture is due to the membrane destabilizing effect on stearylamine. Optimum hypoglycemic effect was observed with a medium acyl-chain lipid (C10). The cumulative hypoglycemic response appeared to correlate inversely with the acyl carbon number of the phospholipid component from C10 to C18. The overall hypoglycemic effect does not appear to change within the liposomal size range of 0.1 micron - 1.98 microns, indicating that insulin absorption following intratracheal instillation is independent of the vesicle size within the range studied. CONCLUSIONS: Phospholipid promoted insulin pulmonary absorption is significantly dependent on the concentration, charge and acyl chain length of the phospholipids.
1. Glucocorticoids are an effective treatment in the amelioration of chronic lung disease in neonates. However, systemic administration of glucocorticoids to neonates is associated with significant side-effects that preclude them as an early intervention to prevent onset of the condition. Conversely, local intratracheal administration of glucocorticoids may prevent inflammatory insult to the lungs without the development of systemic side-effects. We therefore investigated whether local intratracheal delivery of corticosteroids could be facilitated using surfactant as a vehicle. 2. Addition of dexamethasone to either diluted or commercial artificial surfactant, Survanta (Abbott Industries, Sydney, NSW, Australia), did not alter the surface properties of the surfactant. 3. After intratracheal instillation to rats, radiolabelled dexamethasone in Survanta was well distributed throughout all four lobes of the lungs. A concentration gradient of the steroid was observed between the root and the peripheral sections of all lobes. 4. Our results suggest that surfactant is an effective vehicle for intratracheal delivery of glucocorticoids. Moreover, we propose that prophylactic intratracheal administration of glucocorticoids administered shortly after birth may prevent inflammatory insult to the lungs and thereby reduce the likelihood of chronic lung disease developing.
In head-injured adults sudden increases in intracranial pressure (ICP) frequently occur in response to noxious stimuli, such as endotracheal suctioning (ETS). Transient increased ICP may have potentially harmful effects upon head-injured patients. One intervention clinicians believe to be efficacious in blunting ICP response to ETS is administration of lidocaine hydrochloride. This article critiques studies that examined effects of lidocaine in attenuating the ICP response to suctioning and similar stimuli. The literature to date, while providing conflicting results, does demonstrate tentative support for the use of lidocaine prior to ETS as a means of attenuating a rise in ICP. Support was found for the intratracheal route of administration. Additionally when intratracheal lidocaine was coupled with muscle relaxants or other anesthetic agents administered at appropriate times prior to suctioning, large rises in ICP may be effectively blunted.
The aim of the study was to extend existing evidence that intratracheal aerosolization of LPS may serve as a very relevant model to study ARDS. The authors investigated the sequence of pathogenic events reflected by changes in levels of tumor necrosis factor alpha (TNF alpha), surfactant-associated protein A (SP-A) in BAL fluid, in addition to cell count, edema formation, and respiratory function. Within 24 h following intratracheal aerosolization of LPS in the rat, ARDS could be diagnosed according to the lung injury score for patients. This score includes the extent of the inflammatory density on chest X-rays, the severity of hypoxemia, the decline in lung compliance, and the level of PEEP (positive end expiratory pressure). In addition, other typical features of human ARDS appeared to be present in this model: (1) increased microvascular permeability reflected by edema, elevated levels of protein and of LDH, and increased numbers of PMNs in BAL fluid; (2) high levels of TNF alpha in BAL fluid preceding the appearance of PMNs; (3) changes in breathing pattern and a gradual development of respiratory failure with decreased compliance. SP-A levels in BAL fluid doubled within one hour after LPS administration, suggesting that this collectin may play a role in the immediate inflammatory response. Taken together, the findings presented here suggest that intratracheal LPS administration mimics the clinical development of ARDS very closely.
The purpose of this study is to evaluate the effectiveness of lidocaine administered via the endotracheal tube in suppressing cough reflex during anesthetic recovery in children. Fifty ASA class I-II children, aged from 1-5 years old undergoing elective abdominal or urogenital surgery were randomly assigned into two groups. 2% lidocaine 1.5 mg/kg (1ml = 20mg) was administered in group B while normal saline (N/S) 0.1 ml/kg was used in group A (control group). Either one of the agents was instilled into the endotracheal tube right before the end of operation. Airway responses and other associated phenomena were recorded during the recovery period. Recovery condition was categorized into a two-grade categories, namely "good", and "poor" to denote the quality of recovery. Recovery conditions differ significantly between the control group and the experimental group. In group A, 3 patients were classified as the "good" grade but 22 patients were categorized in the "poor" grade. Group B (lidocaine 1.5 mg/kg) has a much better recovery condition than the control group, there were 19 in the "good" grade and only 6 in the "poor" grade. The experimental group treated with 2% lidocaine presented a significantly better recovery than the control group. This effective suppression of the cough reflex might be due to the local anesthetic effect exerted by lidocaine. For the sake of safety all patients were closely followed up at the post anesthesia room until the return of consciousness and laryngeal reflexes. In conclusion, we found that 2% lidocaine 1.5 mg/kg given intratracheally via the endotracheal tube could attenuate cough response during recovery in pediatric anesthesia.
The relationship between the blood coagulation changes after intratracheal injection of heparin and the mast cell population condition was studied. A single intratracheal injection of heparin (3500 U/kg) was found to induce a long-term hypocoagulability effect developing parallel to heparin accumulation by mast cells of the peritoneal and pleural cavities.
The urinary excretion of unmetabolized cyclophosphamide was studied in rats after intratracheal, dermal, oral and intravenous administration. Rats were given two doses of 1 mg kg-1 cyclophosphamide 48 h apart and urine was collected for 96 h after the first treatment. With the help of a phosphor-specific filter in a flame photometer attached to a gas chromatograph, low levels of cyclophosphamide were determined after derivatization with trifluoroacetic anhydride. Cumulative excretion as a percentage of dose ranged from 4.0 to 6.9 after the first dose and 2.7 to 5.5 after the second dose. The highest rate of excretion after the second administration was observed in rats treated intratracheally, while cumulative excretion was higher (6.9%) after the first than after the second (2.7%) intravenous treatment. The most prolonged excretion was observed after dermal application.
A series of long-term inhalation studies of diesel exhaust and intratracheal instillation of diesel particles was conducted on female SPF F344 rats. A particulate but not gaseous component in the inhalation studies provoked inflammatory changes and tumors in the lung, and the intratracheally instilled particles showed similar findings. Adenoma and adenocarcinoma were the main histologic types of the tumors which developed and they showed the phenotype of surfactant apoprotein-producing cells, suggesting that the tumor cell origin was a Type II alveolar cell. The tumor incidence rate correlated with the cumulative concentration of inhaled particles per week and with the amount of particles deposited in the lung. In the instillation studies, the carbon core of diesel particles obtained after exhaustive extraction of tarry matter showed a slightly lower positive rate of lung tumor formation than the rate in untreated diesel particles, indicating an important role of carbon core in the diesel particle-induced tumor. In the intratracheal instillation studies, point mutation of K-ras oncogene was detected in a significant percentage in the tumor cells.
Immunization with peptide P10, derived from gp43, and chemotherapy were used together in an attempt to improve treatment of paracoccidioidomycosis and prevent relapses. The combined treatment showed an additive protective effect when administered at 48 h or 30 days after intratracheal challenge. Its use is recommended to improve regular chemotherapy and reduce the duration of treatment.
1. Tyloxapol, trace-labelled (50-100 microCi/animal) with 3H or 14C, was administered intratracheally in a surfactant formulation (EXOSURF Neonatal) to the male rabbit in a total tyloxapol dose of 5 mg/kg. Urine, faeces, expired air, and blood were collected for up to 10 days following tyloxapol administration. 2. Over 5 days, 3H-tyloxapol-related radioactivity in the urine (13.4%) and faeces (27.4%) accounted for a major fraction of the labelled dose. However, urine also contained an additional 13% of the dose as tritiated water. Expired air accounted for only 4.2% of the dose. At the end of the study, an additional 35.6% of the radioactive dose was found in tissues and the carcass, mainly in the lung (27.4%) and to a lesser extent in the liver (2.8%) and kidney (0.4%). Levels of radioactivity in other tissues, including whole blood, were low. 3. Over a separate 10-day study, faecal (30.4%) and renal (9.7%) elimination of 14C-tyloxapol accounted for 40% of the radioactive dose, with expired air accounting for much less (2.7%). At the end of the study, additional radioactivity was recovered from the lung (43.9%) and to a lesser extent from the liver (3.8%) and kidney (0.3%). The half-life for the elimination of total radioactivity from the lung was estimated to be 10-12 days. 4. These data indicate that, following intratracheal administration, tyloxapol and metabolites were retained by the lung, released slowly into the systemic circulation, and eliminated through faecal and renal excretion.
OBJECTIVE: To study systemic and pulmonary effects of low-dose sildenafil with surfactant in newborn piglets with pulmonary hypertension (PHT) induced by thromboxane A(2) analog (U46619). DESIGN/METHODS: Piglets (1-3 days, 1.7-2.5 kg) were mechanically ventilated and prepared for the continuous measurement of mean systemic and pulmonary arterial pressures (MAP and PAP, respectively), heart rate and pulmonary artery flow (as cardiac output). Following stabilization, PHT was induced by intravenous U46619 infusion (0.2-0.8 microg/kg/min) for 120 min. Piglets were randomized for intratracheal administration of surfactant (BLES, 4 ml/kg) with saline (n=6) or sildenafil (0.05 mg/kg, n=6) given after 60 min of U46619 treatment. Temporal changes of hemodynamic measurements were analyzed by two-way ANOVA. RESULTS: There was progressive PHT induced by U46619 (161% of baseline), with increased PAP and pulmonary vascular resistance and decreased cardiac output. Surfactant and sildenafil combined improved PAP along with reduced pulmonary vascular resistance. Cardiac output was higher with surfactant and sildenafil combined than surfactant alone. No significant changes in heart rate, stroke volume, MAP and systemic vascular resistance were observed. Ratio of PAP:MAP was lowered with surfactant and sildenafil combined. Systemic oxygen consumption was not different between groups but the oxygen extraction ratio was higher than baseline in surfactant alone (P<0.05). CONCLUSIONS: Adding low-dose sildenafil to surfactant is effective in alleviating the progressive PHT developed in newborn piglets induced by thromboxane A(2). Intratracheal sildenafil may be a useful therapeutic adjunct to critically ill neonates with PHT.
Bacterial lipopolysaccharide (LPS) causes acute lung injury (ALI) and contributes to inflammation in the acute respiratory distress syndrome (ARDS) and sepsis, making mechanisms of resistance to LPS critically important in clinical settings. The authors postulated that intratracheal administration of a plasmid (pcDNA3. 0-rTNFalpha) encoding rat tumor necrosis factor-alpha (TNF-alpha) would increase resistance of mice to LPS-induced ALI or mortality. They investigated the time course and dose-response for development of LPS-induced ALI in C57/BL6 mice and sought possible protective effects of 100 microg pcDNA3.0-rTNFalpha intratracheally 1, 2, or 3 weeks before LPS challenge. Lung myeloperoxidase (MPO) activity and alveolar lavage fluid (BALF) cell counts increased significantly 48 hours after intraperitoneal (IP) LPS challenges. After pcDNA3.0-rTNFalpha pretreatment, mice challenged with LPS had lower lung/body weight ratios than mice treated with pcDNA3.0; however, other indices of lung injury did not differ. Survival of mice challenged with lethal IP LPS 2 weeks after intratracheal pcDNA3.0-rTNFalpha vector improved significantly, compared to mice pretreated with the control vector, pcDNA3.0. However, pcDNA3.0-pretreated mice tolerated LPS challenge less well than saline-pretreated controls. LPS causes neutrophilic lung injury and mortality, but pcDNA3.0-TNFalpha does not prevent ALI due to LPS. Intratracheal pcDNA3.0-rTNFalpha pretreatment significantly improves survival of mice after LPS challenge, compared to those pretreated with pcDNA3.0.
BACKGROUND: We previously showed that intratracheal delivery of alloantigen induced prolonged survival of fully allogeneic cardiac grafts in mice. Here, this treatment protocol was combined with nondepleting anti-CD4 monoclonal antibody (mAb) to induce operational tolerance. METHODS: CBA (H-2k) mice were pretreated with intratracheal delivery of whole splenocytes from C57BL/10 (H-2b) mice or a 15-mer Kb peptide, with or without intraperitoneal administration of nondepleting anti-CD4 mAb (YTS177). Seven days later, C57BL/10 hearts were transplanted into the pretreated CBA mice. In addition, some naive CBA mice underwent adoptive transfer of splenocytes from pretreated CBA mice and transplantation of a C57BL/10 heart on the same day. RESULTS: Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time, 12 days). Mice given intratracheal delivery of whole splenocytes or Kb peptide demonstrated prolonged graft survival (median survival time, 84 and 76 days, respectively). Concurrent administration of YTS177 and intratracheal delivery of splenocytes or Kb peptide resulted in indefinite graft survival. Mice with long-surviving C57BL/10 cardiac grafts showed acceptance of skin grafts from C57BL/10 mice but not BALB/c mice, demonstrating that operational tolerance had been induced. Adoptive transfer of splenocytes from mice pretreated with intratracheal delivery of splenocytes or Kb peptide plus YTS177 induced indefinite survival of cardiac grafts in secondary recipients, indicating that regulatory cells had been generated. CONCLUSION: In a murine model, intratracheal delivery of donor splenocytes or Kb peptide combined with YTS177 induced operational tolerance and generated regulatory cells.