Present role of nitric oxide inhalation in severe lung failure.
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Biomedical subjects
Publications and source records attributed to R Rossaint.
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The airway occlusion pressure, P0.1, is the negative airway pressure generated during the first 100 msec of an occluded inspiration. P0.1 is a parameter for the neuro-muscular activation of the respiratory system, which is an important determinant for the work of breathing. It has been shown to be a good predictor for successful weaning from mechanical ventilation. Standard P0.1 measurement techniques are based on a total occlusion of the inspiration for more than 100 msec. These measurements are technically complex and therefore not useful for clinical purposes. Furthermore, a significant breath-by-breath variability has been shown for P0.1, which is neglected by any single point measurement technique. Therefore, we have developed a continuous on-line measurement for breath-by-breath determination of P0.1 using the Siemens Servo 900C respirator. In triggered mechanical ventilation the delay time between the onset of the patient's inspiration and flow delivery from the respiratory is more than 100 msec for this respirator. During that time the inspiration is occluded. Therefore, the trigger effort was proposed to be a good estimate of P0.1. Based on this, we calculated P0.1 as follows: airway pressure (Paw) was registered at the endotracheal tube site of the respiratory tubing, digitized and acquired by a personal computer at 100 Hz. The recorder output of the Servo 900C was connected to the same computer, delivering the electronical signal for the inspiratory valve to open when the inspiratory effort has exceeded the trigger threshold, which needs a minimal delay time of 80 msec. Around 20 msec after this signal flow is delivered from the respirator. The computer runs an algorithm, which recognizes this signal and calculates P0.1 (Servo P0.1) as the slope of the pressure drop during this 100 msec. Paw tracings and the calculated P0.1 values were displayed on the computer screen and stored on disk. This method was validated by comparing it to the standard technique, using a Hans-Rudolph valve for inspiratory occlusion and calculating P0.1 from Paw tracings during the occluded inspiration. For validation we used a mechanical lung model which generated P0.1 values ranging between 1.1-10.3 mbar. For a given adjustment of the lung model two standard measurements (standard P0.1) were made and compared to the Servo P0.1. In a total of 21 measurements the mean Servo P0.1 was 4.9 +/- 2.9 mbar; the mean standard P0.1 was 4.3 +/- 2.5 mbar. The mean difference between Servo P0.1 and standard P0.1 was 0.6 +/- 0.6 mbar (range: -0.3-1.8 mbar). The regression equation for linear regression analysis was: Servo P0.1 = 1.15* standard P0.1-0.05. This correlation was significant (r = 0.99, p < 0.01). From these data we conclude that the described method for continuous P0.1 measurement provides reliable values with the advantage of a maneuver-free, breath-by-breath measurement technique. It thereby opens the possibility for monitoring the neuro-muscular activation of the respiratory system at the bedside, which is shown as an example for a patient during weaning from mechanical ventilation.
The airway occlusion pressure, P0.1, is an index for the neuro-muscular activation of the respiratory system. It has been shown to be a very useful indicator for the ability of patients receiving ventilatory support to be weaned from mechanical ventilation. Since the standard measurement technique for P0.1 determination is technically complex, it is not widely available for clinical purposes. For that reason a P0.1 measurement technique was developed as an integrated function in a standard respirator (Evita, Dräger, Lübeck, Germany). This technique is easy to use and does not need any further equipment. We validated this new technique by comparing it to standard P0.1 measurements in a mechanical lung model as well as in ventilated patients. In the lung model we found a correlation between the Evita measurement and standard measurements of r = 0.99. In 6 ventilated patients the correlation was r = 0.78. Since the Evita P0.1 and the standard measurement had to be performed during two different breaths, this little poorer correlation in patients may be due to a significant breath-by-breath variability in P0.1. Comparing the Evita P0.1 and the standard measurement within one breath resulted in a clearly better correlation (r = 0.89). We conclude that this new measurement technique provides an easy and accurate P0.1 measurement using standard respiratory equipment when tested in a lung model. In patient measurements the method is less precise, which is probably due to the variable waveforms of the inspiratory driving pressure seen in patients, for example when intrinsic PEEP is present.(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVE: To compare the effects of inhaled nitric oxide (NO) and an infusion of prostacyclin (PGI2) on right ventricular function in patients with severe acute respiratory distress syndrome (ARDS). DESIGN: Randomized prospective short-term study. SETTING: Post-surgical ICU in an university hospital. PATIENTS: 10 patients with severe ARDS referred to our hospital for intensive care. INTERVENTIONS: In random sequence the patients inhaled NO at a concentration of 18 parts per million (ppm) followed by 36 ppm, and received an intravenous infusion of PGI2 (4 ng.kg-1.min-1). MEASUREMENTS AND RESULTS: Inhalation of 18 ppm NO reduced the mean (+/- SE) pulmonary artery pressure (PAP) from 33 +/- 2 to 28 +/- 1 mmHg (p = 0.008), increased right ventricular ejection fraction (RVEF), as assessed by thermodilution technique, from 28 +/- 2 to 32 +/- 2% (p = 0.005), decreased right ventricular end-diastolic volume index from 114 +/- 6 to 103 +/- 8 ml.m-2 (p = 0.005) and right ventricular end-systolic volume index from 82 +/- 4 to 70 +/- 5 ml.m-2 (p = 0.009). Mean arterial pressure (MAP) and cardiac index (CI) did not change significantly. The effects of 36 ppm NO were not different from the effects of 18 ppm NO. Infusion of PGI2 reduced PAP from 34 +/- 2 to 30 +/- 2 mmHg (p = 0.02), increased RVEF from 29 +/- 2 to 32 +/- 2% (p = 0.02). Right ventricular end-diastolic and end-systolic volume indices did not change significantly. MAP decreased from 80 +/- 4 to 70 +/- 5 mmHg (p = 0.03), and CI increased from 4.0 +/- 0.5 to 4.5 +/- 0.5 l.min-1.m-2 (p = 0.02). CONCLUSIONS: Using a new approach to selective pulmonary vasodilation by inhalation of NO, we demonstrate in this group of ARDS patients that an increase in RVEF is not necessarily associated with a rise in CI. The increase in CI during PGI2 infusion is probably related to the systemic effect of this substance.
Hemorrhagic disorders due to systemic heparinization are frequent during extracorporeal lung support (veno-venous extracorporeal membrane oxygenation: vv-ECMO). The development of heparin-coated systems has reduced the need for high-dose heparinization. Whereas the use of these heparin-coated membrane lungs and tubings has been described in former studies in adults, only few reports exist in children. This case report describes the application of a heparin-coated extracorporeal system for long-term vv-ECMO in a 13-month-old infant suffering from acute hypoxic respiratory failure after correction of tetralogy of Fallot. Only moderately elevated levels of activated clotting time (ACT, 120-160 s) and activated partial thromboplastin time (aPTT, 40-60 s) were necessary to avoid thrombotic events in the extracorporeal system. Thoracotomies were performed twice without bleeding complications by discontinuation of the systemic heparinization. We conclude that the use of heparin-coated membrane lungs in infants may improve the safety of extracorporeal lung support and permits surgical intervention without major risk of bleeding.
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Continuous intra-arterial blood gas monitoring is a new technique, possibly offering therapeutic advantages through improved monitoring in patients prone to hypoxaemia, hypercapnia and/or respiratory acidosis. Therefore, we studied the clinical applicability, reliability, precision and side effect of long-term continuous intra-arterial blood gas monitoring in patients suffering from severe acute respiratory distress syndrome. In 10 patients continuous intra-arterial blood gas monitoring based on fluorescent optodes technique was performed. At 4 h intervals, arterial blood samples for in vitro blood gas analyses were drawn, stored in ice, and analysed within 3 min. Evaluation of data retrieved from the continuous intra-arterial blood gas monitoring and in vitro blood gas analysis was based on 596 data points using 10 catheters. Average length of insertion was 281 +/- 215 h, max. lengths of stay was 750 h. Arterial blood gas data obtained in vivo were compared to the mean of in vivo and in vitro arterial blood gases. Inter-catheter bias, expressed as percent difference between continuous intra-arterial blood gas and mean in vitro blood gas analysis was 0.19 +/- 0.23% for pH. 1.1 +/- 5.2% for PaCO2 and 1.6 +/- 5.7% for PaO2. No significant gas partial pressure dependent change in precision was demonstrable. There was no significant time dependent drift in sensor precision over the study period. No negative side-effects related to IABG monitoring were observed. We conclude that long-term use of this new device is possible in patients and represents a reliable alternative to conventional in vitro arterial blood gas analysis, when continuous monitoring of blood gases and/or acid-base balance is critical.
In 12 patients undergoing extracorporeal membrane oxygenation for treatment of severe acute respiratory distress syndrome (ARDS), we examined the effects of independent variations in mixed venous oxygen tension (PvO2) and inspired oxygen fraction (FIO2) on the distribution of ventilation and perfusion as assessed by the multiple inert gas elimination technique. Reducing the oxygen concentration of the constant gas stream through the membrane lungs allowed us to decrease the PvO2 by approximately 20 Torr independently of variations in cardiac output and FIO2 as well as to augment FIO2 without influencing PvO2. The interventions did not induce any change in heart rate or systemic or pulmonary hemodynamics. In general, neither during mechanical ventilation at FIO2 of 0.6 nor during mechanical ventilation at FIO2 of 1.0 did the reduced PvO2 cause variations in the distribution of pulmonary blood flow in our patients with severe ARDS. Nevertheless, in individual patients, decreasing PvO2 or ventilation at FIO2 of 1.0 was associated with changes in intrapulmonary shunt. Therefore, we conclude that it is not possible to predict the influence of such interventions in pulmonary gas exchange in the individual patient suffering from ARDS. Differences in the regulation of the local distribution of blood flow caused by the disease itself might explain this phenomenon.
STUDY OBJECTIVE: To investigate the initial and long-term effect of nitric oxide (NO) inhalation in patients with severe acute respiratory distress syndrome (ARDS). DESIGN: Retrospective, clinical study. SETTING: University surgical ICU. PATIENTS: Eighty-seven patients with severe ARDS. INTERVENTIONS AND MEASUREMENTS: Thirty of 87 patients with ARDS inhaled low concentrations of NO for more than 48 h in addition to the standard treatment. Initial and long-term effects of NO inhalation on hemodynamics, gas exchange, and methemoglobin formation were determined. Survival of patients treated with inhaled NO was compared with survival in similar patients without NO inhalation. RESULTS: In 83% of the patients, NO increased the ratio of arterial PO2 to the fraction of inspired O2 (PaO2/FIO2) by > or = 10 mm Hg; in 87%, NO reduced venous admixture (QVA/QT) by > or = 10%, and in 63%, NO decreased mean pulmonary artery pressure (PAP) by > or = 3 mm Hg. Daily short interruption of continuous inhalation of NO for a duration of 17 +/- 2.4 days was consistently associated with a decrease in PaO2/FIO2 by 81 +/- 4 mm Hg (p < 0.001). QVA/QT increased by 8.3 +/- 0.4% (p < 0.001) and PAP by 5.3 +/- 0.3 mm Hg (p < 0.001). Over time, we observed neither tachyphylaxis nor a more pronounced effect of inhaled NO. Methemoglobin increased from 0.74 +/- 0.56% to 0.98 +/- 0.02% (p < 0.001). Survival rates in patients treated with NO did not differ from survival rates in patients not treated with NO. CONCLUSION: Beneficial effects of NO inhalation can be observed in most patients with severe ARDS; in some cases, however, it may fail to improve pulmonary gas exchange or to reduce pulmonary hypertension without obvious explanation. To demonstrate a possible increase in survival associated with NO inhalation, large randomized prospective trials are required.
Despite more than 25 years of extensive research the mortality of ARDS patients remains high. Besides the often deleterious course of the underlying disease, another reason for this high mortality lies in the aggressive ventilatory regimen which is required to maintain arterial blood gases in a more or less normal range. Therapeutic methods which are used to reduce iatrogenic damage to the lungs are pressure controlled ventilation with permissive hypercapnia, differential lung ventilation, positioning therapy, dehydration, and extracorporeal gas exchange with membrane lungs. Nevertheless, many of these patients still die following hypoxaemia or multiple organ failure. Therefore, the need remains to develop new therapeutic strategies and to investigate their influence on the morbidity and mortality of this life-threatening disease. First experiences with nitric oxide (NO) inhalation, intravenous application of antioxidants, intratracheal instillation of surfactant, tracheal gas insufflation and combined fluid/gas ventilation with perfluorocarbon are presented. All these new methods have proved their efficacy, at least in animal studies, however, they should still be regarded as experimental.
The objective of this study was to determine the feasibility and clinical impact of hepatic venous oxygenation monitoring in patients undergoing positive end-expiratory pressure (PEEP) ventilation after OLT. The design comprised a prospective study using repeated-measures design, within an intensive-care unit for liver-transplanted patients in a university hospital. Sixteen consecutive adult patients undergoing orthotopic liver transplantation were enrolled. Postoperatively, a fiber-optic pulmonary artery catheter was inserted into the right hepatic vein. Patients were submitted to controlled ventilation with three different levels of end-expiratory pressure (PEEP): 0, 5 and 10 mbar. Hemodynamics, hepatic venous pressure, mixed venous (SvO2) and hepatic venous oxygenation (SvhO2) were measured. The average time required for hepatic venous catheterization was 2.9 +/- 1.2 min; serious complications were not observed. PEEP 5 mbar did not alter hemodynamics and SvhO2; PEEP 10 mbar significantly reduced cardiac index, SvO2 and widened arteriovenous content difference (p < 0.05). The mean difference between SvO2 and SvhO2 was 6.3 +/- 6.0% and did not change during PEEP ventilation. A significantly positive relationship was observed between SvO2 and SvhO2 (r = 0.91, p < 0.05). Hepatic venous catheterization appeared to be practical and could be utilized to evaluate the effects of therapeutic interventions on the transplanted liver. However, the small number of patients studied will not allow the assessment of any risk-benefit ratio of the technique investigated. Low levels of PEEP provided hemodynamic stability and did not alter hepatic oxygen supply-demand ratio.(ABSTRACT TRUNCATED AT 250 WORDS)
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The relaxing effects of nitric oxide on smooth muscles, first identified in 1987, inaugurated a new area of therapeutic efficacity in intensive care. Nitric oxide is synthesized by endothelial cells, macrophages, brain cells and other cells following immunological activation and plays a role in normal blood pressure homeostasis, neuromodulation, cytotoxicity and intracellular message transmission. Since inappropriate vasodilatation or shock may result from cytokine- or endotoxin-induced overproduction of nitric oxide, experiments have been conducted on the effect of nitric oxide synthase inhibitors on shock-induced hypotension. In animal models, results have demonstrated a new method for treating septic shock since infusing nitric oxide inhibitors can rapidly re-establish haemodynamics. Nevertheless, due to possible interference with the immune defense system further studies on the physiological, pharmacological and metabolic effects are required before routine antishock therapy can be used in the intensive care unit. Inversely, in pulmonary hypertension there may be an insufficient production of endogenous nitric oxide. Thus administration via inhalation would represent a promising replacement therapy. In addition, since nitric oxide is rapidly inactivated by haemoglobin, its vasodilatory effect is restricted to the pulmonary vasculature resulting in lowered pulmonary artery pressure without systemic vasodilatation. Effective protocols have been developed for primary pulmonary hypertension of the newborn and acute respiratory distress syndrome. The bronchodilatory effect of nitric oxide is another area suggesting an alternative approach to treating different causes of bronchoconstriction including asthma. The results of early clinical trials are awaited. When used in low concentrations under continuous monitoring, nitric oxide is a safe new therapeutic option for the treatment of pulmonary hypertension and nitric oxide inhibitors may have an important role to play in the management of septic shock.
Exogenous nitric oxide (NO) reduces pulmonary vascular resistance after low-dose inhalation in patients. To estimate endogenous NO synthesis in the upper respiratory tract, we measured inhaled and exhaled NO in volunteers and patients during spontaneous or controlled ventilation, respectively. 20.3 nmol per min NO was synthesised in the nasopharynx of non-smoking volunteers, leading to autoinhalation of 0.07-0.13 NO parts per million during inspiration; smokers had reduced NO synthesis. In volunteers, 50-70% of the NO was resorbed by the lungs; ventilated patients were deprived of NO autoinhalation. Bacteria in the nose may take part in endogenous NO synthesis.
Bacterial and fungal infections are a major cause of morbidity and mortality after orthotopic liver transplantation. In the immunocompromised host, infections are thought to arise from the gut, which is almost always colonized with potential pathogens. Using oral selective bowel decontamination (SBD), potential pathogens can be eradicated from the gut and infections prevented. In this catamnestic study we have reviewed gastrointestinal colonization, bacterial and fungal infections, and bacterial resistance to standard antibiotics in our first 206 liver transplant patients while under SBD. With few exceptions, gram-negatives were eradicated from the gastrointestinal tract and secondary colonization was inhibited. In spite of unsatisfactory elimination of Candida, probably because nystatin doses were too low, Candida infections were rare (n = 4) and none was fatal. One and two-year survival rates were 93% and 92%, respectively. The bacterial and fungal infection rate was 27.8% with an infection-related mortality of 1.95%. Infections with aerobic gram-positive bacteria prevailed and only 11 gram-negative and 11 fungal infections occurred; among the latter, Aspergillus and Mucor were the most serious and responsible for three of the six deaths in this series. With regard to the development of resistance, we found an increasing number of enterococci and coagulase-negative staphylococci resistant to ciprofloxacin and imipenem, respectively, but unlikely as a consequence of SBD.
We report about our first experiences with a new device for continuous intra-arterial monitoring of blood gases in a patient with severe acute respiratory failure. This device facilitated continuous monitoring of PaO2, PaCO2 and pH while weaning the patient from extracorporeal membrane oxygenation (ECMO). Although sufficient oxygenation at FIO2 0.45 could be achieved after disconnection from ECMO, carbon dioxide elimination remained inadequate and resulted in severe respiratory acidosis. Within six hours, PaCO2 increased to 95 mmHg. Continuous monitoring of pH and PaCO2 helped to monitor CO2 retention and assisted the decision making process for reinstitution of ECMO.