Response to inhaled nitric oxide in acute lung injury depends on distribution of pulmonary blood flow prior to its administration

Responses to inhaled nitric oxide (iNO) in acute lung injury (ALI), as evidenced by improvements in oxygenation, are variable. We hypothesized that the effect of iNO may be related to the pre-iNO distribution of pulmonary blood flow (PBF). In the present study we evaluated the effect of iNO on PBF in normal healthy dogs and in a canine model of ALI induced by oleic acid (OA). In Group "OA only" (n = 5), ALI was induced by central venous injection of 0.08 ml/kg OA. In Group "E+OA" (n = 5), hypoxic pulmonary vasoconstriction after ALI was blocked with low-dose endotoxin (15 microg/kg of Escherichia coli endotoxin) administered 30 min before giving the same dose of OA. Measurements of regional PBF and lung water concentration (LWC) using positron emission tomography (PET) and H215O were performed before and after OA or placebo, and then again at concentrations of 10, 40, and 0 ppm iNO. One hundred twenty minutes after OA injury, PaO2/FIO2 fell significantly in Group OA only, from 567 +/- 32 to 437 +/- 67 mm Hg. In these animals, PBF redistributed from the dorsal edematous regions of the lungs to the nondependent zones, thus partially preserving normal ventilation/ perfusion relationships. As in the normal animals, in Group OA only, iNO did not significantly change either PBF or oxygenation. In Group E+OA, the administration of low-dose endotoxin eliminated perfusion redistribution from the dorsal edematous lung regions. As a result, PaO2/FIO2 fell from 558 +/- 70 to 119 +/- 53 mm Hg, a decrease that was significantly greater than that in Group OA only. In Group E+OA, administration of iNO restored perfusion redistribution to a similar level as in Group OA only, which was associated with a significant improvement in PaO2/FIO2, from 119 +/- 53 to 251 +/- 159 (10 ppm iNO), and 259 +/- 165 mm Hg (40 ppm iNO). We conclude that the effect of iNO on oxygenation after ALI depends on the pre-iNO perfusion pattern, which may help explain the variable response to iNO often observed in patients with acute respiratory distress syndrome.     

Experimental antitumour activity of S 16020-2 in a panel of human tumours

OBJECTIVE: To compare the effects of inhaled nitric oxide (NO) and extracorporeal membrane oxygenation (ECMO) on oxygenation, hemodynamics, and lymphatic drainage in an oleic acid lung injury model in sheep. DESIGN: Prospective, randomized study. SETTING: Animal research laboratory. ANIMALS: Thirty female sheep, weighing 35 to 40 kg. INTERVENTIONS: Acute lung injury was induced by central venous injection of oleic acid (0.5 mL/kg body weight). A chronic lymph fistula had been prepared through a right thoracotomy 3 days before the experiment. Animals were assigned randomly to the NO group (n = 14) or the ECMO group (n = 16). When a lung injury score of > 2.5 was achieved, the animals were given NO in dosage increments of 2, 5, 10, 20, and 40 parts per million (ppm), or placed on ECMO with an FIO2 of 0.21 (ECMO-21) and then 1.0 (ECMO-100) at the oxygenator. Mechanical ventilator parameters were kept constant to isolate the effects of NO and ECMO on systemic and pulmonary hemodynamics, cardiac output, oxygenation parameters, lymph/plasma protein ratio, and lymph flow. Measurements and calculations were performed after 1 hr at each individual step of NO concentration or FIO2. MEASUREMENTS AND MAIN RESULTS: In the ECMO group, PVRI and MPAP did not change and were significantly different from the NO group. In the NO group, there was a dose-dependent decrease in venous admixture, maximal at 10 ppm NO and decreasing from 40 +/- 6% to 23 +/- 10% (p < .05). This decrease was significantly different from the ECMO group, where there was no change. There was a significant increase in PaO2/FIO2 in the NO group, maximal at 10 ppm NO (84 +/- 11 to 210 +/- 90, p < .05), but a greater increase in PaO2/FIO2 on ECMO-21 (81 +/- 14 to 265 +/- 63) and a further increase on ECMO-100 (398 +/- 100) (p < .05). The lymph/plasma protein ratio remained unchanged in both groups after induction of lung injury by oleic acid. However, lymph flow decreased by 11 +/- 6% in the NO group, whereas it increased by 14 +/- 17% in the ECMO group (p < .05). CONCLUSIONS: In an oleic acid-induced sheep model of acute lung injury, there were significant differences between the effects of NO and ECMO on acute pulmonary hypertension, hypoxemia, hypercarbia, and lymph flow. NO significantly decreases pulmonary hypertension, whereas pulmonary hemodynamics were not substantially affected by ECMO. Both interventions reversed hypoxemia, but ECMO did so to a greater degree, and only ECMO improved hypercarbia. Only NO decreased lymph flow, possibly as an effect of decreased microvascular filtration pressure. This study did not attempt to evaluate the impact of these interventions on ventilatory requirements, barotrauma, or outcome. However, this model suggests that NO therapy may moderate pulmonary hypertension and improve lymph flow in acute lung injury. Clinical studies are needed to assess whether NO therapy might be beneficial in treatment of severe acute lung injury in older children and adults.     

Intravenous almitrine combined with inhaled nitric oxide for acute respiratory distress syndrome. The NO Almitrine Study Group

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator and intravenously administered almitrine, a selective pulmonary vasoconstrictor, have been shown to increase PaO2 in patients with acute respiratory distress syndrome (ARDS). This prospective study was undertaken to assess the cardiopulmonary effects of combining both drugs. In 48 consecutive patients with early ARDS, cardiorespiratory parameters were measured at control, after iNO 5 ppm, after almitrine 4 micrograms. kg-1. min-1, and after the combination of both drugs. In 30 patients, dose response to 2, 4, and 16 micrograms. kg-1. min-1 of almitrine with and without NO was determined. Almitrine and lactate plasma concentrations were measured in 17 patients. Using pure O2, PaO2 increased by 75 +/- 8 mm Hg after iNO, by 101 +/- 12 mm Hg after almitrine 4 micrograms. kg-1. min-1, and by 175 +/- 18 mm Hg after almitrine combined with iNO (p < 0.001). In 63% of the patients, PaO2 increased by more than 100% with the combination of both drugs. Mean pulmonary artery pressure (Ppa) increased by 1.4 +/- 0.2 mm Hg with almitrine 4 micrograms/kg/ min (p < 0.001) and decreased by 3.4 +/- 0.4 mm Hg with iNO and by 1.5 +/- 0.3 mm Hg with the combination (p < 0.001). The maximum increase in PaO2 was obtained at almitrine concentrations <= 4 micrograms. kg-1. min-1, whereas almitrine increased Ppa dose-dependently. Almitrine plasma concentrations also increased dose-dependently and returned to values close to zero after 12 h. In many patients with early ARDS, the combination of iNO 5 ppm and almitrine 4 micrograms. kg-1. min-1 dramatically increases PaO2 without apparent deleterious effect allowing a rapid reduction in inspired fraction of O2. The long-term consequences of this immediate beneficial effect remain to be determined.     

Early response to inhaled nitric oxide and its relationship to outcome in children with severe hypoxemic respiratory failure

OBJECTIVE: To examine whether the early response to inhaled nitric oxide (iNO) is a measure of reversibility of lung injury and patient outcome in children with acute hypoxemic respiratory failure (AHRF). DESIGN: Retrospective review study. SETTING: Pediatric ICUs. PATIENTS: Thirty infants and children, aged 1 month to 13 years (median, 7 months) with severe AHRF (mean alveolar arterial oxygen gradient of 568+/-9.3 mm Hg, PaO2/fraction of inspired oxygen of 56+/-2.3, oxygenation index [OI] of 41+/-3.8, and acute lung injury score of 2.8+/-0.1). Eighteen patients had ARDS. INTERVENTIONS: The magnitude of the early response to iNO was quantified as the percentage change in OI occurring within 60 min of initiating 20 ppm iNO therapy. This response was compared to patient outcome data. MEASUREMENTS AND RESULTS: There was a significant association between early response to iNO and patient outcome (Kendall tau B r=0.43, p < 0.02). All six patients who showed < 15% improvement in OI died; 4 of the 11 patients (36%) who had a 15 to 30% improvement in OI survived, while 8 of 13 (61%) who had a > 30% improvement in OI survived. Overall, 12 patients (40%) survived, 9 with ongoing conventional treatment including iNO, and 3 with extracorporeal support. CONCLUSIONS: In AHRF in children, greater early response to iNO appears to be associated with improved outcome. This may reflect reversibility of pulmonary pathophysiologic condition and serve as a bedside marker of disease stage.     

High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation

OBJECTIVE: We investigated whether a treatment according to a clinical algorithm could improve the low survival rates in acute respiratory distress syndrome (ARDS). DESIGN: Uncontrolled prospective trial. SETTING: One university hospital intensive care department. PATIENTS AND PARTICIPANTS: 122 patients with ARDS, consecutively admitted to the ICU. INTERVENTIONS: ARDS was treated according to a criteria-defined clinical algorithm. The algorithm distinguished two main treatment groups: The AT-sine-ECMO (advanced treatment without extracorporeal membrane oxygenation) groups (n = 73) received a treatment consisting of a set of advanced non-invasive treatment options, the ECMO treatment group (n = 49) received additional extracorporeal membrane oxygenation (ECMO) using heparin-coated systems. MEASUREMENTS AND RESULTS: The groups differed in both APACHE II (16 +/- 5 vs 18 +/- 5 points, p = 0.01) and Murray scores (3.2 +/- 0.3 vs 3.4 +/- 0.3 points, p = 0.0001), the duration of mechanical ventilation prior to admission (10 +/- 9 vs 13 +/- 9 days, p = 0.0151), and length of ICU stay in Berlin (31 +/- 17 vs 50 +/- 36 days, p = 0.0016). Initial PaO2/FIO2 was 86 +/- 27 mm Hg in AT-sine-ECMO patients that improved to 165 +/- 107 mm Hg on ICU day 1, while ECMO patients showed an initial PaO2/FIO2 of 67 +/- 28 mm Hg and improvement to 160 +/- 102 mm Hg was not reached until ICU day 13. QS/QT was significantly higher in the ECMO-treated group and exceeded 50% during the first 14 ICU days. The overall survival rate in our 122 ARDS patients was 75%. Survival rates were 89% in the AT-sine ECMO group and 55% in the ECMO treatment group (p = 0.0000). CONCLUSIONS: We conclude that patients with ARDS can be successfully treated with the clinical algorithm and high survival rates can be achieved.     

Dramatic effect on oxygenation in patients with severe acute lung insufficiency treated in the prone position

OBJECTIVE: To confirm the positive effect of prone positioning on oxygenation in patients with acute lung insufficiency. DESIGN: Clinical follow-up study. SETTING: The intensive care unit at a tertiary care academic hospital. PATIENTS: Thirteen patients suffering from severe acute lung insufficiency caused by trauma, septicemia, aspiration, and burn injury. Eleven of the patients had severe hypoxia (oxygenation indices [PaO2/FIO2] < or = 80 torr [< or = 10.7 kPa]). Patients > 70 yrs of age were excluded from the study. INTERVENTIONS: Treatment in the prone position without changing other ventilatory settings than FIO2 when saturation increased. MEASUREMENTS AND MAIN RESULTS: Twelve of the 13 patients responded to treatment in the prone position. The patient that did not respond improved her gas exchange when nitric oxide was instituted. She died, however, from a Gram-negative septicemia. No patient needed extracorporeal membrane oxygenation. Apart from the settings of FIO2 when saturation increased, the ventilatory settings were unchanged. In the prone position, the oxygenation index increased (p < .0002) and the alveolar-arterial oxygen gradient, P(A-a)O2, decreased dramatically (p < .0001). CONCLUSIONS: The prone position significantly improves impaired gas exchange due to severe acute lung insufficiency. It is suggested that this treatment is used before more complex modalities.     

Inhaled nitric oxide in patients with cystic fibrosis during preoperative evaluation and during anaesthesia for lung transplantation

INTRODUCTION: Inhaled nitric oxide (iNO) has been recently used as pulmonary vasodilator without any systemic effects because of a rapid inactivation by haemoglobin. We studied haemodynamic and oxygenation effects during iNO administration in cystic fibrotic patients during preoperative evaluation and during anaesthesia for lung transplantation. METHODS: From March 1996 to November 1997, 35 patients received iNO (40 ppm) during preoperative evaluation in spontaneously breathing. 13 patients, who underwent double lung transplantation, received iNO (40 ppm) during the surgical procedures, after pulmonary artery clamping. RESULTS: In the preoperative evaluation a significant decrease of mean pulmonary artery pressure, pulmonary vascular resistance index and intrapulmonary shunt, with an increase of PaO2/FiO2, were observed during iNO administration, compared to baseline in 100% O2. During lung transplantation a significant decrease in intrapulmonary shunt was noted. All the transplants were successfully performed without cardio-pulmonary bypass. In all procedures, after iNO administration, we observed no modification of systemic haemodynamics. In conclusion, our study confirms the pulmonary effects of iNO without any systemic effects in patients affected by cystic fibrosis during preoperative evaluation and during anaesthesia for lung transplantation.     

Effectiveness of nitric oxide inhalation in septic ARDS

STUDY OBJECTIVE: To evaluate the percentage of nitric oxide (NO) responders in septic shock patients with ARDS. Additionally, to investigate long-term NO effects on cardiac performance and oxygen kinetic patterns in NO responders vs nonresponders. DESIGN: Prospective cohort study. SETTING: ICU of a university hospital. PATIENTS: Twenty-five consecutive patients with a diagnosis of septic shock and established ARDS requiring inotropic and vasopressor support. INTERVENTIONS: After diagnosis of ARDS, NO was administered at 18 or 36 ppm. Patients demonstrating a NO-induced rise of arterial oxygen tension of 20% or more and/or a fall in mean pulmonary artery pressure of 15% or more were grouped as NO responders; others were grouped as nonresponders. MEASUREMENTS AND RESULTS: Ten patients (40%) were NO responders, while 15 patients (60%) were nonresponders. Mortality was 40% in NO responders and 67% in nonresponders (NS). NO responders developed a significantly lower mean pulmonary artery pressure (28 +/- 6 vs 33 +/- 6 mm Hg; p < 0.05), lower pulmonary vascular resistance (PVR: 258 +/- 73 vs 377 +/- 163 dyne.s.cm-5.m-2; p < 0.05), and higher PaO2/FIO2 ratio (192 +/- 85 vs 144 +/- 74 mm Hg; p < 0.05) within the study period. In responders, NO-induced afterload reduction resulted in increased right ventricular ejection fraction (RVEF: 40 +/- 7 vs 35 +/- 9%; p < 0.05), significantly higher cardiac index (CI: 4.5 +/- 1.1 vs 4.0 +/- 1.2 L.min-1.m-2; p < 0.05) and oxygen delivery (DO2: 681 +/- 141 vs 599 +/- 160 mL.min-1.m-2; p < 0.05) compared with nonresponders. In NO nonresponders, RVEF was correlated with PVR, CI, DO2, mixed venous oxygen saturation (SvO2), and oxygen extraction ratio (O2ER) (r = +/- 0.60 to +/- 0.69; p < 0.05). No significant correlation between RVEF and any of these parameters was observed in responders. SvO2 (75 +/- 7 vs 69 +/- 8%; p < 0.05) and O2ER (0.24 +/- 0.06 vs 0.27 +/- 0.06; p < 0.05) were significantly different between responders and nonresponders, while no difference in oxygen consumption was observed (161 +/- 41 vs 153 +/- 43 mL.min.m-2). CONCLUSIONS: Inhaled NO is effective in only a subgroup of septic ARDS patients, with a higher, but insignificantly different percentage of survivors in the responder group. NO responders were characterized by increased RVEF accompanied by higher CI, DO2, and lower O2ER. In nonresponders, RVEF remained depressed, with a close correlation between RVEF and CO as well as DO2 and O2ER. Thus, nonresponders seem to suffer from impaired cardiac reserves and correspondingly lower oxygen transport variables.     

Hemodynamic profile in severe ARDS: results of the European Collaborative ARDS Study

OBJECTIVE: Although the acute respiratory distress syndrome (ARDS) was identified as long as 30 years ago, potential therapeutic objectives have been defined from small series rather than large trials. Moreover, relationships between ARDS and hemodynamics are unclear. The European Collaborative ARDS Study was designed to identify factors influencing the pathogenesis, severity, and prognosis of ARDS. Analysis of the hemodynamic profiles collected during this study and of their contribution to the above-mentioned facets of ARDS is the focus of the present report. DESIGN: Prospective clinical study. SETTING: 38 European intensive care units (ICUs). PATIENTS AND METHODS: We collected 2758 sets of data from 586 patients, including baseline data, data on proven or suspected causes of ARDS differentiating direct and nondirect lung injury, and data on baseline status including multiple organ dysfunction (MOD) with differentiation of primary ARDS from ARDS secondary to severe systemic disorders. Events during follow-up were also recorded, including whether the acute respiratory failure did or did not improve after 24 h (groups A and B, respectively). When available, hemodynamic data were recorded at enrollment (day 0), on days 1-3, 7, 14, and 21, and at discharge or at the time of death in the ICU. RESULTS: Although the rate of pre-existing disease and the nature and rate of complications varied widely among etiologic categories, differences in the hemodynamic profile occurred only between primary and secondary ARDS. Both at inclusion and during the course of the illness, variables that were used to investigate Va/Q mismatch [arterial oxygen tension (PaO2, arterial oxygen saturation, right-to-left shunt, and the PaO2/fractional inspired oxygen (FIO2) ratio] predicted survival. High pulmonary artery pressure (PAP) and low systemic artery pressure (SAP) were also related to the prognosis. In the logistic regression model including hemodynamic and oxygen-related variables, however, the only independent predictors of survival were the ratio of right over left ventricular stroke work (RVSW/LVSW) and the PaO2/FIO2 ratio at admission. On day 2, the best prognostic model included: age [odds ratio (OR) = 1.04, p = 0.0004], opportunistic pneumonia as the cause of ARDS (OR = 3.2, p = 0.03), existence of MOD (OR = 1.9, p = 0.03), PaO2/FIO2 (OR = 0.96, p = 0.005), and RVSW/LVSW (OR = 25, p = 0.02). A high RVSW/LVSW ratio, high systolic PAP, low diastolic SAP, and low PaO2/FIO2, and increased right atrial pressure were negative prognostic indicators during follow-up. CONCLUSION: In addition to the cause of ARDS and the early time-course of lung function, a high systolic PAP and a low diastolic SAP were strong independent indicators of survival.     

High expression of leptin by human bone marrow adipocytes in primary culture

Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10-80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51+/-21 vs 23+/-17, P < .0001) or term infants with idiopathic or acute respiratory distress syndrome (45+/-20 vs 20+/-17, P < .0001), 'idiopathic' PPHN (39+/-14 vs 14+/-9, P < .0001), and sepsis (55+/-25 vs 26+/-20, P < .0001) provided there was no associated refractory shock. Improvement in oxygenation was less significant and sustained (OI=41+/-16 vs 28+/-18, P < .001) in term neonates with meconium aspiration syndrome and much less (OI=58+/-25 vs 46+/-32, P < .01) in those with congenital diaphragmatic hernia. Only 21 of the 129 term newborns (16%) required extracorporeal membrane oxygenation (57% survival). Survival was significantly associated with the magnitude in the reduction in OI at 30 min of iNO therapy, a gestational age > or =34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants.     

Traumatic uveitis: the problem of pathogenetic therapy

Inhalative nitric oxide (NO) has recently been included in the therapeutic armament for the treatment of ARDS. We evaluated the effect of inhalative NO on hemodynamic and oxygen transport parameters in 30 internal intensive care patients suffering from ARDS. All patients received a pulmonary artery catheter. Hemodynamics were assessed prior to NO therapy and after 1, 6, 12, and 24 h. 80% (n = 24) of the patients were classified as therapy responders. The median NO dose was 15 ppm (range 5 to 40 ppm). The PaO2/FiO2--ratio increased significantly after initiation of NO (p = 0.0002) while the pulmonary shunt fraction (Qs/Qt) decreased significantly (p = 0.0019). All other measured or calculated parameters including arterial and pulmonary arterial blood pressure remained unchanged. No negative effects of the therapy could be observed. Inhalative NO improves oxygenation in most intensive care patients with ARDS and thus offers the possibility to reduce invasiveness of mechanical ventilation.     

Measurement of lung volume and DLCO in acute respiratory failure

We have undertaken rebreathing measurements of functional residual capacity (FRC), carbon monoxide diffusing capacity (DLCO), and diffusing coefficient (KCO) during positive pressure ventilation in 15 patients with adult respiratory distress syndrome (ARDS). Measurements of oxygenation (PaO2:FIO2 ratio) and lung injury score (LIS) were also recorded. Eight patients subsequently died (mortality of 53%). There was no significant difference in mean FRC, PaO2:FIO2, or LIS at presentation between survivors and nonsurvivors. However, both DLCO and KCO at presentation were significantly greater in survivors than nonsurvivors. In a separate study of nine patients with less severe lung injury, pulmonary capillary blood volume, derived from values of DLCO measured at two different values of FIO2, correlated with invasive pulmonary vascular resistance (PVR) measurements (r = 0.84, p < 0.01). DLCO measurements can be successfully undertaken in patients being ventilated with acute lung injury and may be a useful, noninvasive method of assessing the pulmonary circulation. The lowest values of DLCO were recorded in patients who subsequently did not survive.     

Inhaled nitric oxide inhibits human platelet aggregation, P-selectin expression, and fibrinogen binding in vitro and in vivo

BACKGROUND: Recent data suggest that inhaled NO can inhibit platelet aggregation. This study investigates whether inhaled NO affects the expression level and avidity of platelet membrane receptors that mediate platelet adhesion and aggregation. METHODS AND RESULTS: In 30 healthy volunteers, platelet-rich plasma was incubated with an air/5% CO2 mixture containing 0, 100, 450, and 884 ppm inhaled NO. ADP- and collagen-induced platelet aggregation, the membrane expression of P-selectin, and the binding of fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptor were determined before (t0) and during the 240 minutes of incubation. In addition, eight patients suffering from severe adult respiratory distress syndrome (ARDS) were investigated before and 120 minutes after the beginning of administration of 10 ppm inhaled NO. In vitro, NO led to a dose-dependent inhibition of both ADP-induced (3+/-3% at 884 ppm versus 70+/-6% at 0 ppm after 240 minutes; P<.001) and collagen-induced (13+/-5% versus 62+/-5%; P<.01) platelet aggregation. Furthermore, P-selectin expression (36+/-7% of t0 value; P<.01) and fibrinogen binding (33+/-11%; P<.01) were inhibited. In patients with ARDS, after two who did not respond to NO inhalation with an improvement in oxygenation had been excluded, an increase in plasma cGMP, prolongation of in vitro bleeding time, and inhibition of platelet aggregation and P-selectin expression were observed, and fibrinogen binding was also inhibited (19+/-7% versus 30+/-8%; P<.05). CONCLUSIONS: NO-dependent inhibition of platelet aggregation may be caused by a decrease in fibrinogen binding to the platelet GP IIb/IIIa receptor.     

Genetic variation at the short tandem repeat loci HumvWA, HumFXIIIB, and HumFES/FPS in the Egyptian and Yemenian populations

Eighteen head-injured patients undergoing hyperventilation were studied for changes in jugular venous oxygen saturation (SjvO2) and arteriovenous oxygen content difference (AVDO2) in response to changes in PaO2 and PaCO2. SjvO2 decreased significantly from 66% +/- 3% to 56% +/- 3% (mean +/- SD) when PaCO2 decreased from 30 to 25 mm Hg at a PaO2 of 100-150 mm Hg. SjvO2 values returned to baseline (66% +/- 2%) when PaCO2 was restored to 30 mm Hg. Repetition of the study at a PaO2 of 200-250 mm Hg produced a similar pattern. However, SjvO2 values were significantly greater with PaO2 within the range of 200-250 mm Hg (77% +/- 4% and 64% +/- 3%) than SjvO2 measured at a PaO2 of 100-150 mm Hg at PaCO2 values of both 30 and 25 mm Hg. AVDO2 also improved with a PaO2 of 200-250 mm Hg at each PaCO2 (P < 0.001). In conclusion, decreases in SjvO2 associated with decreases in PaCO2 may be offset by increasing PaO2. IMPLICATIONS: The adequacy of cerebral oxygenation can be estimated in head-injured patients by monitoring jugular bulb oxygen saturation and the arteriovenous oxygenation content difference. Increasing the partial pressure of arterial oxygen above normal offset deleterious effects of hyperventilation on jugular bulb oxygen saturation and arteriovenous oxygenation content difference in head-injured patients.     

Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios

OBJECTIVE: We determined whether inhaled nitric oxide (NO) could improve systemic oxygenation in human neonates with hypoplastic lungs. METHODS: A multicenter nonrandomized investigation was performed to study the efficacy of short-term NO inhalation. Inhaled NO was administered at 80 ppm to nine neonates without evidence of structural cardiac disease by echocardiography. Lung hypoplasia was due to congenital diaphragmatic hernia (CDH) in eight patients and to oligohydramnios in one patient. A total of 15 trials of NO inhalation were performed in these nine patients. Eight trials in seven patients were performed before extracorporeal membrane oxygenation ((ECMO); one patient had two trials) and seven trials were performed in five patients after decannulation from ECMO (two patients had two trials each). RESULTS: NO inhalation before ECMO did not change postductal PaO2 (42 +/- 3 mmHg vs 42 +/- 4 mmHg), oxygen saturation (SpO2; 89% vs 88%) or oxygenation index (31 +/- 4 cm H2O/torr vs 31 +/- 4 cm H2O/torr) for the group. All patients required ECMO support, which lasted from 5 to 17 days (mean 9). After decannulation from ECMO, NO inhalation increased postductal PaO2 from a median of 56 mm Hg (range 41 to 94) to a median of 113 mm Hg (range 77 to 326), P < .05. It decreased the oxygenation index from a median of 23 cm H2O/torr (range 11 to 7) to a median of 11 cm H2O/torr (range 4 to 21), P < .05. It increased SpO2 from 91% to 96% (P < .05) and pH from 7.48 +/- .03 to 7.50 +/- .03. CONCLUSION: In our patients with hypoplastic lungs, inhaled NO was effective only after ECMO. This could be due to maturational changes such as activating the endogenous surfactant system. Inhaled NO may be effective in neonates with hypoplastic lungs who have recurrent episodes of pulmonary hypertension after ECMO, even if they were previously unresponsive.     

Aortic root disease and valve disease associated with ankylosing spondylitis

STUDY OBJECTIVES: The use of inhaled nitric oxide (NO) in the management of patients with ARDS has become widespread, although not all patients respond to this form of support. The aim of this study was to examine the relationship of responsiveness to inhaled NO and features of underlying disease. DESIGN: Prospective observational study. SETTING: The ICU of a university-affiliated, tertiary referral hospital. PATIENTS: Twenty-six adult patients with established ARDS. INTERVENTIONS: Conventional support for multiple organ failure, plus inhaled NO. MEASUREMENTS AND RESULTS: Response to inhaled NO was assessed, and ARDS was characterized in terms of pulmonary morphology (scoring of high-resolution CT); inflammation (BAL neutrophil count and plasma myeloperoxidase concentration); and markers of lung injury severity (oxygenation deficit and pulmonary vascular resistance [PVR]). Fourteen patients responded to NO and 12 did not. There were no differences between the two groups in terms of CT score, inflammatory status, baseline oxygenation deficit, lung injury score, or PVR. Additionally, there was no difference in survival between responders and nonresponders. Patients who developed ARDS after thoracic surgery were significantly more likely to die than other patients (relative risk 4.1, p < 0.01). The oxygenation deficit and lung injury score correlated better with the extent of ground-glass opacification than with the volume of consolidated lung tissue. CONCLUSION: We were unable to identify features of disease likely to be associated with a clinically useful response to inhaled NO therapy using the parameters studied.     

Polygraphic validation of distraction tasks in clinical differential tremor diagnosis

We studied the effect of inhaled nitric oxide (NO) on 80 patients who had undergone cardiac surgery in our center. The indications for receiving NO inhalation and the number of patients were as follows: Pp/Ps > 0.5 for pulmonary hypertension (PH) (n = 32; 21 children and 11 adults), severe PH crisis (n = 9), high pulmonary vascular tone (Glenn pressure more than 18 mm Hg after bidirectional Glenn operation) or arterial oxygen saturation (SaO2) less than 70% despite an FiO2 of 1.0 after Blalock-Taussig shunt (n = 6), mean pulmonary artery pressure (PAP) > 15 mm Hg and transpulmonary gradient (TPG) (mean PAP - left atrial pressure [LAP]) > 8 mm Hg after Fontan-type operation (n = 18), elevated pulmonary vascular tone (mean PAP > 30 mm Hg and left ventricular assist system [LVAS] flow rate < 2.5 L/min/m2) in patients with LVAS (n = 3), and impaired oxygenation (PaO2/FiO2 < 100 under positive end-expiratory pressure [PEEP] > 5 cm H2O) (n = 12). Low dose inhaled NO (10 ppm) had the following effects. In adult PH patients, it significantly reduced the mean PAP (from 37.3 to 27.0 mm Hg; average values are given) and increased the mean systemic arterial pressure (SAP) (64.7 to 75.3 mm Hg). In infant PH patients, it increased the mean SAP (51.8 to 56.1 mm Hg). In patients with a PH crisis, it significantly reduced the central venous pressure (CVP) (13.3 to 8.8 mm Hg) while increasing both the mean SAP (49.4 to 57.9 mm Hg) and PaO2/FiO2 (135 to 206). In patients after a Fontan-type operation, it significantly reduced the mean PAP (16.8 to 13.8 mm Hg) and TPG (9.5 to 5.8 mm Hg). In patients under LVAS, it reduced the CVP (11.7 to 8.0 mm Hg) and mean PAP (32.0 to 24.7 mm Hg). In impaired oxygenation patients, PaO2/FiO2 was increased (75 to 106). Sixty-five patients were all followed for 2.0-4.3 years (average, 3.1 years). All 65 patients remained free from oxygen requirement, and possible chronic adverse effects including the occurrence of malignant tumors or chronic inflammation in the respiratory tract were not observed.     

Sustained pulmonary vasodilation after inhaled nitric oxide for hypoxic pulmonary hypertension in swine

It has been shown that pulmonary vasodilation is sustained after discontinuation of inhaled nitric oxide (INO) during moderate hypoxic pulmonary hypertension (HPH) in swine. The present investigations demonstrated how INO dose, hypoxia duration, and endogenous NO production influence this important phenomenon. Fifteen adolescent Yorkshire swine were randomly assigned to three groups (n = 5 each) and underwent the following phasic experimental protocol: (I) Baseline ventilation (FIO2 = .3); (II) Initiating HPH (FIO2 = .16 to .18, PaO2 = 45 to 55 mm Hg); (III) INO at 10 ppm; (IV) Posttreatment observation; (V) INO of 80 ppm; and (VI) Posttreatment observation. Phase II (pretreatment hypoxia) lasted 30 minutes in group A (short hypoxia) and 120 minutes in group B (long hypoxia). N-nitro-L-arginine methyl ester (NAME) was used to inhibit nitric oxide synthase (NOS) throughout the experiment in group C (short hypoxia + NAME). Hemodynamics and blood gases were monitored by systemic and pulmonary artery catheters placed by femoral cutdown. Analysis of variance with post-hoc adjustment was used to compare groups at each phase, and the paired t test was used for comparisons within a group. With respect to baseline mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR), there were no significant differences among the three groups. MPAP and PVR were significantly higher in group C than in group A during phase II, (MPAP, 76% +/- 8% v 33% +/- 2%; PVR, 197% +/- 19% v 78% +/- 10%; P < .05). There were no significant differences in MPAP or PVR during phases III through VI. When MPAP was expressed as percent dilation, 80 ppm caused significantly more dilation than did 10 ppm in all three groups. Groups A and C had significantly higher sustained pulmonary artery dilation after 80 ppm than after 10 ppm (A, 82% +/- 31% v 17% +/- 11%; C, 68% +/- 10% v 42% +/- 12%; both P < .05), but group B did not (43% +/- 15% v 30% +/- 9%; P = .25). High dose results in stronger vasodilation than low dose during and after INO for moderate HPH of short duration. Long hypoxia blunts this high-dose advantage. Endogenous NO inhibition augments HPH but does not decrease pulmonary vasodilation during or after INO.     

Is there a role for video-assisted thoracoscopy in the staging of non-small cell lung cancer?

OBJECTIVE: To evaluate the effects of prolonged neuromuscular blockade (NMB) on oxygenation and duration of mechanical ventilation in children with respiratory failure. DESIGN: Retrospective case control study. SETTING: The pediatric intensive care unit (PICU) of a tertiary university hospital. PATIENTS: All children (n = 68) in the PICU ventilated for pulmonary parenchymal disease for 3 days or longer over a 4 1/2 year period. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Diagnoses, pediatric risk of mortality scoring, indications for, and duration of, mechanical ventilation and neuromuscular blockade, and blood gas data with corresponding ventilator parameters were extracted from the medical records. Twenty-eight patients received NMB at the initiation of mechanical ventilation and this was continued for 72 h or longer. Cessation of NMB was associated with a significant improvement in ventilator parameters and oxygenation index. The subset of children with respiratory syncytial virus disease (RSV) receiving prolonged NMB had longer ventilator courses compared to those in whom NMB was not used, despite similar demographics, severity of illness and oxygenation impairment. CONCLUSIONS: Stopping NMB is associated with a rapid improvement in oxygenation and prolonged use of NMB in children with RSV is associated with a protracted ventilatory course. DEFINITION: Oxygenation index (OI)*: Mean Airway Pressure x FiO2 x 100/PaO2* Higher scores represent deterioration in oxygenation.     

Acute effects of inhaled nitric oxide in adult respiratory distress syndrome

This study evaluated the dose-response effect of inhaled nitric oxide (NO) on gas exchange, haemodynamics, and respiratory mechanics in patients with adult respiratory distress syndrome (ARDS). Of 19 consecutive ARDS patients on mechanical ventilation, eight (42%) responded to a test of 10 parts per million (ppm) NO inhalation with a 25% increase in arterial oxygen tension (Pa,O2,) over the baseline value. The eight NO-responders were extensively studied during administration of seven inhaled NO doses: 0.5, 1, 5, 10, 20, 50 and 100 ppm. Pulmonary pressure and pulmonary vascular resistance exhibited a dose-dependent decrease at NO doses of 0.5-5 ppm, with a plateau at higher doses. At all doses, inhaled NO improved O2 exchange via a reduction in venous admixture. On average, the increase in Pa,O2, was maximal at 5 ppm NO. Some patients, however, exhibited maximal improvement in Pa,O2 at 100 ppm NO. In all patients, the increase in arterial O2 content was maximal at 5 ppm NO. The lack of further increase in arterial O2 content above 5 ppm partly depended on an NO-induced increase in methaemoglobin. Respiratory mechanics were not affected by NO inhalation. In conclusion, NO doses < or =5 ppm are effective for optimal treatment both of hypoxaemia and of pulmonary hypertension in adult respiratory distress syndrome. Although NO doses as high as 100 ppm may further increase arterial oxygen tension, this effect may not lead to an improvement in arterial O2 content, due to the NO-induced increase in methaemoglobin. It is important to consider the effect of NO not only on arterial oxygen tension, but also on arterial O2 content for correct management of inhaled nitric oxide therapy.