Inhaled nitric oxide and acute lung injury.

The nitric oxide (NO) field has been one of the most exciting scientific ventures over the past 10 years. Among the researches developed, the use of inhalation of NO gas allowed us to propose this therapy in lung diseases with promising results. Because of its property as a "selective" pulmonary vasodilator and because of its apparent clinical safety, inhaled NO has been proposed in acute lung injury (ALI) to improve severe hypoxemia. In this situation, the abnormal ventilation-perfusion ratio is improved by inhaled NO, limiting arterial hypoxia. The major clinical trials performed in adults, however, have failed to show any benefit on mortality and on mechanical ventilation requirements. Inhaled NO has been shown as an efficient therapy in pediatric ALI, probably because of a lower comorbidity. Because of the inhaled NO uptake by the lung, the extra vascular lung effects might be in the future the most important development in relation with platelet anti-agregant and anti-inflammatory properties.

Inhaled nitric oxide fraction is influenced by both the site and the mode of administration.

OBJECTIVE: Inhaled nitric oxide (NO) can be delivered continuously or sequentially (= during inspiration) at different locations of the ventilation circuit. We have tested the influence of locations, modes of NO administration and the ratio of the inspiratory time over the respiratory cycle time (I/I + E ratio) on the accuracy of NO fractions, delivered by 2 devices: Opti-NO and Flowmeter. METHODS: We used a simplified lung model consisting of a ventilation circuit with a Y piece, a tracheal tube, a 150 ml dead-space volume and a 5 liter balloon. Three fractions (3, 6, 9 ppm) were administered continuously or sequentially, in controlled volume, in 4 different sites on the inspiratory branch above the Y piece: i) just after the water trap, ii) just before the Y piece; below the Y piece: iii) just after the Y piece, iv) into the endotracheal tube. In addition, different I/I + E ratios (25, 33, 50, 80%) were studied. The delivered NO fractions were measured in the balloon by chemiluminescence (CLD 700, Ecophysics). A linear regression analysis was used to test the relationship between administered and measured NO fractions for the 3 fractions (3, 6 and 9 ppm) in sequential and continuous modes. Intercept values were compared to zero and slopes to the identity line. RESULTS: When NO was administered in the continuous mode upstream the Y piece, NO fractions measured in the balloon corresponded to the administered fractions. In contrast, below the Y piece, the measured NO fractions were significantly lower than the administered NO fractions. In the sequential mode, above and below the Y piece, the delivered NO fractions were within the manufacturer's range. CONCLUSIONS: For the continuous NO delivery, locations above the Y piece are mandatory. However, locations below the Y piece imposes a sequential system, which can also be used for the sites located above the Y piece.

Nitric oxide and almitrine: the definitive answer for hypoxemia.

Hypoxia-induced by acute lung injury results from abnormal ventilation/perfusion ratio distribution towards shunt or low ventilation/perfusion zones. Pharmacological modification of pulmonary blood flow distribution improving ventilation/perfusion ratio should correct hypoxia. The development of inhaled nitric oxide therapy had confirmed this concept, but with a relatively high proportion of 'non responders'. Then development of other drugs used alone or in association with nitric oxide may reinforce the benefit of nitric oxide. This has been tested with almitrine bismesylate, a lipophilic drug that reinforce hypoxic pulmonary vasoconstriction. Using inhaled nitric oxide in combination with almitrine, several studies in adult respiratory distress syndrome or acute lung injury patients have shown spectacular results in term of PaO2 and pulmonary shunt reduction. Moreover, the proportion of responders to this combination seems largely great than those observed for each drug alone. In conclusion, pulmonary blood flow manipulation improving ventilation/perfusion mismatching is one of the major strategies to correct severe hypoxia.

Alveolar neutrophil oxidative burst and beta2 integrin expression in experimental acute pulmonary inflammation are not modified by inhaled nitric oxide.

It was recently proposed that nitric oxide (NO) inhalation interferes with polymorphonuclear neutrophil (PMN) activation status during acute pulmonary inflammation, although variable results have been observed considering timing of NO administration, species, and model differences. After intratracheal administration of lipopolysaccharide (LPS) in rats, we characterized pulmonary inflammatory reaction (lung wet, dry, and wet to dry weights) and, using flow cytometry, the activation status (H2O2 production and beta2 integrin CD11b/CD18 expression) of PMN obtained from blood and from bronchoalveolar lavage (BAL). Eight hours after LPS injection, rats received for an additional 10 h, at a same Fio2 (85%), either 15 parts per million NO or the same gas flow of nitrogen. We found that 18 h after LPS, lung wet, dry, and wet-to-dry weights, H2O2 production, and CD11b/CD18 expression were increased. PMN obtained from BAL were highly activated as evidenced by an already maximal expression of the beta2 integrin CD11b/CD18, whereas the high H2O2 production at basal state could be further enhanced after ex vivo stimulation. Blood PMN were not different from control cells at basal state; however, their increased capacity to be stimulated ex vivo suggested an in vivo priming effect of intratracheal LPS. In conclusion, inhaled NO, given with a high FiO2, in the presence of this established endotoxinic lung injury did not reverse the markers of PMN activation studied nor lung edema formation in this rat model.

Noninvasive monitoring of cardiac output in critically ill patients using transesophageal Doppler.

Measurement of cardiac output using thermodilution technique in mechanically ventilated patients is associated with significant morbidity. The goal of the present study was to assess the validity of cardiac output measurement using transesophageal Doppler in critically ill patients. Forty-six patients from three different intensive care units underwent 136 paired cardiac output measurements using thermodilution (COTH) and transesophageal Doppler (COTED). In addition, simultaneous suprasternal Doppler and indirect calorimetry (Fick principle) were used to measure cardiac output in 26 patients from one center. A good correlation was found between COTH and COTED (r = 0.95), with a small systematic underestimation (bias = 0.24 L/min) using transesophageal Doppler. The limits of agreement between COTH and COTED were +2 L/min and -1.5 L/min. Variations in cardiac output between two consecutive measures using either transesophageal Doppler or thermodilution techniques were similar in direction and magnitude (bias = 0 L/min; limits of agreement = +/-1.7 L/min). Suprasternal Doppler and indirect calorimetry yielded similar correlations and agreements in the subset of patients in whom they were used. These results confirm that transesophageal Doppler can provide a noninvasive, clinically useful estimate of cardiac output and detect hemodynamic changes in mechanically ventilated, critically ill patients.

Continuous jugular bulb venous oxygen saturation validation and variations during intracranial aneurysm surgery.

PURPOSE: During intracranial aneurysm surgery, numerous factors may alter cerebral blood flow and oxygen supply-demand balance. Continuous monitoring of jugular bulb venous oxygen saturation (SvjO2) may help in the anesthetic management of such procedures. MATERIALS AND METHODS: Fiberoptic SvjO2 was continuously monitored in seven patients during intracranial aneurysm surgery. Fiberoptic SvjO2 measurement was compared with IL3 CO-OXIMETER determination from 85 paired samples. The occurrence of large SvjO2 variations (SvjO2 variation reaching 10% or more of stable preceding value) during aneurysm surgery was recorded and classified according to the association or not with systemic clinical or therapeutic changes. RESULTS: Fiberoptic SvjO2 showed a limited accuracy, with limits of agreement with IL3 CO-OXIMETER at -16.8% and +10.7% and a small bias (-3.1%). SvjO2 variations were frequent during aneurysm surgery, ranging from 3 to 22 per patient during procedures lasting 6 hours (range 4.5 to 7). Half of these variations occurred in the absence of any systemic clinical or therapeutic change, most often leading to an increased SvjO2. CONCLUSIONS: Although the accuracy of fiberoptic SvjO2 determination is limited, it allows the detection of cerebral blood flow and oxygen supply-demand imbalance during aneurysm surgery. The frequent occurrence of SvjO2 elevations is suggestive of reactive hyperemia mechanisms.

[Monitoring head trauma]. / Monitorage du traumatisme crânien.

Cerebral monitoring after head trauma aims at reducing secondary lesions resulting mainly from additional cerebral ischemia-hypoxia. Such monitoring must include repetitive (preferably continuous) estimation of cerebral blood flow, cerebral oxygenation and their variations. Based on this information the evaluation and modulation of the main determinants of cerebral blood flow (cerebral metabolism, cerebral perfusion pressure, arterial oxygen content and PaCO2 variations) often allows optimization of cerebral blood flow and metabolism balance. This therapeutic strategy may lead to improvement of severe head trauma outcome through reduction of additional cerebral ischemia-hypoxia.

Alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation.

It was recently demonstrated that nitric oxide (NO) inhalation improves arterial oxygenation in patients with the adult respiratory distress syndrome (ARDS). However, the potential adverse reaction of NO on inflammatory cells and mediators in the lung has not yet been investigated. In this study, we evaluated the impact of NO inhalation on lung polymorphonuclear neutrophil (PMN) activation and proinflammatory cytokine release, both of which are involved in the pathophysiology of ARDS. Two groups of patients with ARDS of similar etiologies were compared; one received NO (n=9) and the other did not (n=5). After 4 d of NO inhalation (18 ppm), PMN form bronchoalveolar lavage (BAL) showed a reduction in both spontaneous H2O2 production (p<0.05) and beta 2 integrin CD11b/CD18 expression (p<0.05). Moreover, the high levels of IL8 and IL-6 decreased in BAL fluid supernatants after NO inhalation (p<0.05). In the NO-untreated group of patients with ARDS, neither PMN activation nor levels of IL-8 and IL-6 in BAL fluid changed significantly on Day 4. These results suggest that NO inhalation might reduce lung inflammation in ARDS, as reflected by PMN activation status and IL-8/IL-6 release.

Renal hemodynamic and functional effect of PEEP ventilation in human renal transplantations.

Increased intrathoracic pressure with positive pressure breathing (PPB) induces renal hypoperfusion and excretion function impairment the mechanism of which may be partially related to reflex sympathetic nerve activation. The consequences of renal denervation on PPB-induced renal impairment are unknown. This study was conducted to evaluate the effects of increasing intrathoracic pressure with positive end-expiratory pressure (PEEP) on renal blood flow (RBF, pulsed Doppler implantable microprobes) and function in 12 kidney transplantation recipients during the immediate post-transplantation period. Three sets of measurements were performed during successively zero end-expiratory pressure (ZEEP), 15 cm H2O PEEP, and back to ZEEP. PEEP ventilation was associated with mean arterial pressure (MAP) and cardiac output (CO) decrease (-12%, p < 0.01; -26%, p < 0.01, respectively). RBF remained constant in the three protocol conditions. PEEP ventilation was associated with a decrease in urinary output (8.5 +/- 5.6 versus 12.9 +/- 8.6 ml/min; p < 0.01), urinary sodium concentration (115 +/- 14 versus 121 +/- 12 mmol/L; p < 0.01) sodium excretion rate (1 +/- 0.7 versus 1.6 +/- 1.1 mmol/min; p < 0.01), and creatinine clearance (17.1 +/- 10 versus 23.2 +/- 13.6 ml/min; p < 0.01). PEEP-induced urinary output decrease was correlated to renal perfusion pressure decrease (r = 0.7, p = 0.016). These results suggest that despite denervation and renal blood flow stability, renal handling of water and salt is perfusion pressure-dependent during PEEP in human renal allograft recipients.

Interactions between hemodynamic and hormonal modifications during PEEP-induced antidiuresis and antinatriuresis.

The interactions between hemodynamic and hormonal modifications during antidiuresis and antinatriuresis induced by positive end-expiratory pressure (PEEP) were studied in six patients under 15 cm H2O PEEP before PEEP and after the addition of lower body positive pressure (LBPP) to PEEP (PEEP+LBPP). We measured or calculated the following: cardiac index, systemic arterial, right atrial, pulmonary arterial, and pulmonary artery occlusive pressures; indexed renal blood flow (iodohippurate 131 sodium clearance); total blood volume (chromium 51 radiolabeled RBCs); glomerular filtration rate; urinary output; fractional excretion of sodium (FE Na+); plasma concentrations of antidiuretic hormone (ADH), plasma renin activity (PRA), norepinephrine and epinephrine; urinary concentration of PGE2 (PGE2u). Although LBPP application corrected PEEP deleterious effects on systemic and renal hemodynamics, sustained fall in Vu and in FE Na+ were observed. Antidiuresis was not due to ADH release. Sympathetic activation and high PRA appeared the main determinants of renal function alterations in PEEP ventilation.

Effect of modifying nitric oxide pathway on liver circulation in a rabbit endotoxin shock model.

The role of nitric oxide (NO) inhibition on liver circulation during sepsis is unknown. To answer this question, we studied the effects of L-arginine (the substrate for the NO synthase), linsidomine (a direct NO donor), and N omega-nitro-L-arginine (an NO inhibitor) on the liver circulation in anesthetized rabbits previously injected with endotoxin (Escherichia coli, Salmonella enteridis, and Salmonella minnesota, 400 micrograms each). After endotoxin administration, and without fluid resuscitation, rabbits showed a hypodynamic shock with decrease in mean arterial pressure (MAP) and aortic blood flow velocity. Portal vein blood flow velocity decreased, whereas hepatic artery blood flow velocity increased. Saline or treatments were injected, 75 min after endotoxin administration. In saline-treated rabbits, MAP, aortic and portal vein blood flow velocities remained steady but hepatic artery blood flow velocity decreased. Only N omega-nitro-L-arginine (7.5 mg/kg, intravenously) significantly increased MAP compared to saline treatment. However, aortic, portal vein, and hepatic artery blood flow velocities were lower in rabbits treated with N omega-nitro-L-arginine than in saline-treated rabbits. L-Arginine (600 mg/kg, intravenously) increased aortic blood flow and portal vein blood flow velocity with no change on hepatic artery blood flow velocity. In contrast, linsidomine (1 mg) increased both hepatic flows. These results show that NO inhibition after endotoxin injection reduces systemic and liver flows, while NO release from linsidomine improves them. These findings question the usefulness of NO inhibition during septic shock, particularly as hepatic failure frequently occurs in the evolution of the disease.

Portal and hepatic arterial blood flow measurements of human transplanted liver by implanted Doppler probes: interest for early complications and nutrition.

Hepatic artery thrombosis and early acute rejection are severe complications of orthotopic liver transplantation (OLT). Their rapid detection is most desirable. The purpose of this study was to assess the usefulness of monitoring hepatic artery (HABF) and portal vein (PVBF) blood flows during the first week after OLT. At the end of operation, microprobes were sutured to the vessels, and their connecting tubes were externalized and connected to a pulsed Doppler flowmeter operating at 8 MHz. In 10 patients (ages ranged from 2 to 54 years) of 106, measurements of HABF and PVBF were done during alternative clamping of both vessels and before and after abdominal closure, every 12 hours during 7 days, and at day 7, before and after a 150 gm carbohydrate meal. At day 7 the probes were pulled out by gentle traction without complication, and all patients were allowed to go home. Reciprocal increase of flow during selective clamping was only observed for HABF (+45.8% +/- 47.6%; p less than 0.01). Abdominal closure decreased both HABF and PVBF by 13.8%, p less than 0.01, and 26%, p less than 0.05, respectively. In seven cases no significant variation of HABF and PVBF was observed during 7 days. In two patients with histologically confirmed early acute rejection, a marked decrease of diastolic HABF, without modification in PVBF, was the first manifestation and was rapidly corrected by boluses of steroids. In one patient disappearance of systolic and diastolic HABF led us to diagnose an arterial obliteration caused by a plicature, which was successfully surgically treated in the emergency department. In all patients, after oral ingestion of the carbohydrate meal, and only after this type of diet, a significant and deep decrease (-87%, p less than 0.001) of HABF was observed between 7 and 120 minutes without any change in PVBF. Such an effect was not observed in control patients. We conclude that this Doppler flowmetric technique with implantable microprobes is useful for rapid diagnosis of and strategy in treating early complications and is a new tool for pathophysiologic study of OLT consequences.

Evaluation of pulsed Doppler common carotid blood flow as a noninvasive method for brain death diagnosis: a prospective study.

Among the main causes for the relatively small number of organ donors, the delay in the diagnosis of brain death plays a major role. This prospective study was designed to evaluate whether pulsed Doppler mean and phasic common carotid blood flow (CCBF) combined with arterial and jugular venous blood gases could rapidly and specifically establish a diagnosis of brain death. CCBF was measured by an 8 MHz pulsed Doppler flowmeter, allowing measurement of the vessel diameter via a double transducer probe, which fixed the ultrasonic incidence angle. From an initial series of patients (n = 28) with an established diagnosis [brain death n = 14; severe coma with a Glasgow Coma Scale (GCS) less than 7, n = 14], the results of the logistic regression analysis process yielded the most discriminating parameters for brain death diagnosis: end-diastolic velocity (Ved - 1.4 vs. 12.7 cm/s; t = 7.67, P = 0.001) and blood flow (Qed - 13.6 vs. 121.4 ml/min). These parameters were then tested in a blind fashion on a second series of 28 comatose patients (GCS = 7). They resulted in correct diagnosis (brain death n = 14 or severe coma n = 14) for all patients. Brain death diagnosis was confirmed by clinical signs, EEG, and/or angiography. From the analysis of the overall population (n = 56), a value of Qed of less than 31.4 ml/mn indictes brain death. The authors conclude, that pulsed Doppler measurements of CCBF represent an early, low cost and noninvasive technique, the results of which may prompt legally accepted procedures, which in turn would reduce the delay required before brain death is diagnosed. Moreover, this technique could help in deciding on discontinuation of active therapy in severely injured patients.

No involvement of antidiuretic hormone in acute antidiuresis during PEEP ventilation in humans.

Decreased urinary output (Vu ml/min) after institution of PEEP is attributed to a variety of mechanisms including decreased cardiac output and renal blood flow (RBF), activation of neurohormonal reflexes, increased catecholamines, plasma renin activity (PRA), and antidiuretic hormone (ADH) release. To evaluate these factors, seven normovolemic patients (36 yr +/- 13 SD), free of preexisting lung, cardiac, or renal disease, requiring continuous mandatory ventilation for neurologic reasons were studied. The authors measured or calculated: total blood volume (TBV) (51Cr); right atrial, pulmonary arterial, pulmonary wedge, and systemic pressures, cardiac index (CI); renal plasma flow (RPF) (iodohippurate sodium 131I [131I PAH] clearance); glomerular filtration rate (GFR) (creatinine clearance), free water clearance (CH2O), osmolal clearance (Cosm), fractional excretion of sodium (FENa+) and potassium (FEK+); and plasma renin activity (PRA) (ng X ml-1 X h-1), plasma ADH (pg/ml; radioimmunoassay), epinephrine (E in pg/ml), and norepinephrine (NE in pg/ml) (double-isotope radioenzymatic assay). Two conditions were studied after 90-min steady state: 1) zero PEEP (ZEEP); and 2) 15 cmH2O PEEP. PEEP caused a significant decrease in CI (-21%; P less than 0.01) and RPF (-19%; P less than 0.05) without significant decrease in GFR. A significant decrease in Vu (-55%; P less than 0.05), FENa+ (-39%; P less than 0.05) and Cosm (-36%; P less than 0.25) occurred without modification in CH2O. Plasma ADH remained in the normal range and did not increase when PEEP was applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic, gas exchange, and hormonal consequences of LBPP during PEEP ventilation.

Hemodynamic, gas exchange, and hormonal response induced by application of a 25- to 40-mmHg lower body positive pressure (LBPP), during positive end-expiratory pressure (PEEP; 14 +/- 2.5 cmH2O) were studied in nine patients with acute respiratory failure. Compared with PEEP alone, LBPP increased cardiac index (CI) from 3.57 to 4.76 l X min-1 X m-2 (P less than 0.001) in relation to changes in right atrial pressure (RAP) (11 to 16 mmHg; P less than 0.01). Cardiopulmonary blood volume (CPBV) measured in five patients increased during LBPP from 546 +/- 126 to 664 +/- 150 ml (P less than 0.01), with a positive linear relationship between changes in RAP and CPBV (r = 0.88; P less than 0.001). Venous admixture (Qva/QT) decreased with PEEP from 24 to 16% (P less than 0.001) but did not change with LBPP despite the large increase in CI, leading to a marked O2 availability increase (P less than 0.001). Although PEEP induced a significant rise in plasma norepinephrine level (NE) (from 838 +/- 97 to 1008 +/- 139 pg/ml; P less than 0.05), NE was significantly decreased by LBPP to control level (from 1,008 +/- 139 to 794 +/- 124 pg/ml; P less than 0.003). Plasma epinephrine levels were not influenced by PEEP or LBPP. Changes of plasma renin activity (PRA) paralleled those of NE. No change in plasma arginine vasopressin (AVP) was recorded. We concluded that LBPP increases venous return and CPBV and counteracts hemodynamic effects of PEEP ventilation, without significant change in Qva/QT. Mechanical ventilation with PEEP stimulates sympathetic activity and PRA apparently by a reflex neuronal mechanism, at least partially inhibited by the loading of cardiopulmonary low-pressure reflex and high-pressure baroreflex. Finally, AVP does not appear to be involved in the acute cardiovascular adaptation to PEEP.