Peter J. Papadakos

Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome : Results of a randomized phase II trial

OBJECTIVES To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed. DESIGN Prospective, multicenter, randomized, double-blind, placebo-controlled study. SETTING Intensive care units of 30 academic, teaching, and community hospitals in the United States. PATIENTS Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization. INTERVENTIONS Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm. MEASUREMENTS AND MAIN RESULTS Acute increases in PaO2, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygenation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a PaO2 increase > or =20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at day 28 (a post hoc analysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemoglobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm. CONCLUSIONS From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.

Low sensitivity of the anion gap as a screen to detect hyperlactatemia in critically ill patients.

The anion gap is commonly used as a screening test for the presence of lactic acidosis. Analysis of the distribution of anion gaps for 56 adult surgical ICU patients with peak blood lactate levels greater than or equal to 2.5 mmol/L showed the anion gap to be an insensitive screen for elevated lactate in a critically ill, hospitalized population. All patients (11/11) with a peak lactate greater than or equal to 10 mmol/L had an anion gap greater than or equal to 16 mmol/L; however, 50% (6/12) of patients with lactates between 5.0 and 9.9 mmol/L and 79% (26/33) of those with lactates between 2.5 and 4.9 mmol/L had anion gaps less than 16 mmol/L. Hyperlactatemia was associated with considerable mortality at all levels: 100% among patients with lactate levels greater than or equal to 10 mmol/L, 75% between 5.0 and 9.9 mmol/L, and 36.4% between 2.5 and 4.9 mmol/L. Acidosis (pH less than 7.30) did not significantly alter mortality by lactate level. The observation that, for 57% of patients in this study, an elevated lactate level was not accompanied by an elevated anion gap suggests that hyperlactatemia should be included in the differential diagnosis of nonanion gap acidosis.

Surfactant therapy for acute lung injury/acute respiratory distress syndrome.

Purpose of reviewCurrently, three phase III surfactant replacement trials for acute lung injury (ALI)/acute respiratory distress syndromes (ARDS) patients are underway. Although the efficacy of surfactant replacement therapy will first have to be proved in these phase III trials, recent reports indicate some enticing possibilities for the future of surfactant therapy. Recent findingsPatients requiring mechanical ventilation show alterations in their endogenous surfactant composition. Depending on the type of lung injury or the elapsed time, modifications to surfactant preparations could enhance the efficacy of these preparations. Surfactants that closely resemble natural surfactant, especially those containing surfactant proteins (SP-B/C) and nonphospholipids (cholesterol), are able to restore normal surfactant physiology. Furthermore, lipids that are able to withstand degradation by lipases could further enhance surfactant therapy. SummaryIf surfactant therapy fulfills the promises expected from the ongoing phase III trials, future surfactant preparations may even enhance therapy efficacy and restore the altered endogenous surfactant pool as soon as possible.

Dopexamine hydrochloride in septic shock : effects on oxygen delivery and oxygenation of gut, liver, and muscle

It has been suggested that septic shock is a disorder of microvascular autoregulation. Tissue blood flow is modulated by the state of activation of upstream endothelial receptors controlling the vascular smooth muscle tone. Because vascular receptor populations vary between organs, it should be expected that vasoactive drugs affect tissue oxygenation differently in different organs. We studied the effects of dopexamine HCl (a novel inotrope) and septic shock on oxygen delivery as well as tissue Po2 in gut, liver, and skeletal muscle in anesthetized rabbits. Employing the thermodilution technique, cardiac output was measured across the pulmonary bed and used to calculate oxygen delivery. Three eight-channel Mehrdraht Dortmund Oberfläche oxygen electrodes were placed on gut serosa, liver, and skeletal muscle surfaces, respectively, and sufficient readings were obtained to calculate tissue Po2 distributions. During septic shock mean arterial pressure, cardiac output, oxygen delivery, and mean tissue Po2 decreased in all organs. Our results suggest that the observed changes in tissue oxygenation during septic shock were caused by defective regulation of microvascular blood flow. In conclusion, during baseline conditions dopexamine HCl caused no statistically significant changes in tissue oxygenation in any organ, except in skeletal muscle at 10 micrograms/kg/min when tissue Po2 increased. During septic shock, however, dopexamine HCl improved oxygenation in all three organs in a dose-dependent manner.

Respiratory failure and hypoxemia in the cirrhotic patient including hepatopulmonary syndrome

Purpose of review Liver cirrhosis and portal hypertension present with three unique pulmonary complications that are the subject of ongoing clinical research: hepatopulmonary syndrome, portopulmonary hypertension (POPH), and hepatic hydrothorax. The present article is based on a review of the current literature on how to manage these disorders, which are highly important to both anesthesiologists and intensive care physicians. Recent findings Hepatopulmonary syndrome leads to progressive hypoxemia through diffuse vasodilatation of the pulmonary microcirculation. Liver transplantation, although associated with increased mortality, is the only viable treatment. POPH occurs when vascular remodeling triggers an increase in pulmonary artery pressure and resistance. The role of liver transplantation in POPH is controversial given the excessive mortality in patients with moderate to severe POPH. Medical treatment is able to decrease pulmonary artery pressures, though multicenter randomized controlled trials showing improved outcome are lacking to date. Ultrasound plays an increasingly important role in the diagnosis of all three conditions. Summary Patients with end-stage liver disease are at risk for respiratory failure and hypoxemia and need to be screened for hepatopulmonary syndrome, POPH, and hepatic hydrothorax. Failure to timely recognize and adequately treat these complications of cirrhosis may have severe consequences.

Effect of mortality rate on the performance of the Acute Physiology and Chronic Health Evaluation II: a simulation study.

ObjectiveTo evaluate the impact of case mix variation on the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) II using measures of calibration and discrimination. DesignAPACHE II data were collected prospectively at the surgical intensive care unit of the University of Vermont on all adult admissions over an 8-yr period (excluding cardiac surgical patients, burn patients, and patients <16 yrs of age). The original case mix was systematically varied to create 2,000 different case mixes ranging in mortality between 5% and 18% using a computer-intensive resampling algorithm. The area under the receiver operating characteristic curve and the Hosmer-Lemeshow C statistic were derived for each of the simulated case mixes with bootstrapping. SettingThe surgical intensive care unit at a 450-bed teaching hospital. PatientsA group of 6,806 adult surgical patients excluding cardiac surgical patients and burn patients. Measurements and ResultsSimulated data sets were created from a database of patients treated at a single institution to test the hypothesis that the performance of APACHE II is stable across a clinically reasonable range of mortality rates. The discrimination and calibration of APACHE II varied with case mix. ConclusionThe discrimination of APACHE II is not independent of case mix. However, the variability of the Hosmer-Lemeshow statistic as a function of the case mix may simply reflect the limitations of this goodness of fit statistic to assess model calibration. Because the discrimination of APACHE II is a function of case mix, caution should be exercised when using APACHE II-based adjusted mortality rates to compare intensive care units with widely divergent case mixes.

Additives in intravenous anesthesia modulates pulmonary inflammation in a model of LPS-induced respiratory distress

Background: It has been suggested that propofol with ethylenediaminetetraacetic acid (EDTA) can modulate the systemic inflammatory response. Prolonged higher levels of pulmonary inflammation are associated with poor outcome of patients with acute lung injury. In the present study, we hypothesized that pulmonary inflammation could be modulated by propofol with EDTA compared with propofol with sulfite.

Parenteral hydralazine revisited

Historical aspects of the development and application of the vasodilator hydralazine are reviewed. The pharmacology, pharmacokinetics, metabolism, and mechanism of action are discussed, with emphasis on the parenteral use of this drug. It is reiterated that parenteral hydralazine is the preferred drug for the treatment of severe preeclampsia, but its usefulness in other forms of accelerated hypertension is also addressed. Through comparisons with other established antihypertensive agents, the efficacy and pharmacoeconomic potential of hydralazine are stressed.

The use of pressure-controlled inverse ratio ventilation in the surgical intensive care unit.

A key element in the treatment of Adult Respiratory Distress Syndrome (ARDS) is improvement in oxygen delivery to match metabolic demands. Conventional modes of ventilation have decreased mortality (50%) very little. We have done a retrospective analysis of 30 surgical patients who were treated with pressure-controlled inverse ratio ventilation. Mortality was 10%. Arterial oxygenation improved from 40.8 +/- 12.2 mm Hg to 138 +/- 47.2 mm Hg, while PCO2 decreased from 37.8 +/- 7.6 mm Hg to 31.1 +/- 5.9 mm Hg. Simultaneously, with the use of pressure-controlled inverse ratio ventilation, minute ventilation could be decreased by 30%, which may be secondary to increased O2 delivery to the tissue. Our data indicate that pressure-controlled inverse ratio ventilation may be beneficial to surgical patients with ARDS.

A double-blind placebo-controlled study to evaluate the safety and efficacy of L-2-oxothiazolidine-4-carboxylic acid in the treatment of patients with acute respiratory distress syndrome.

Objective:Acute respiratory distress syndrome is an abrupt inflammatory illness that involves damage from reactive oxygen species. We examined the efficacy and safety of oxothiazolidine-4-carboxylic acid (OTZ), a free radical scavenger, in treating acute respiratory distress syndrome. Design:Double-blind, placebo-controlled trial. Setting:Multicentered study. Patients:Patients with a Pao2/Fio2 ≤200 and bilateral infiltrates on chest radiograph, and requiring mechanical ventilation. Interventions:We randomized 215 patients to receive OTZ, 210 mg/kg per day every 8 hrs for 14 days or placebo. Measurements and Main Results:Ventilator-free days (the number of days alive and free from ventilator requirement) during the first 30 days of study were 8.3 vs. 13.5 days for the OTZ and placebo groups, respectively (p < .001). Mortality was 30/101 (29.7%) in the OTZ group and 18/114 (15.8%) in the placebo group during the 30-day study period (p = .014). This study was terminated prematurely for safety reasons after 215 of the planned 352 patients were enrolled. Conclusions:OTZ does not improve survival or reduce ventilator time in patients with acute respiratory distress syndrome and may worsen outcome, although mortality in the OTZ group was similar or lower than most similar trials. Alternatively, our results may be best explained by the unusually excellent outcome in the placebo group.