Stefan Lundin

Metabolism and excretion of nitric oxide in humans. An experimental and clinical study.

Despite the increasing insight in the clinical importance of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF), there is limited information about the metabolism and elimination of this mediator in humans. We studied the degradation of NO in healthy subjects inhaling 25 ppm for 60 minutes and in patients with severe heart failure inhaling 20, 40, and 80 ppm in consecutive 10-minute periods. In other healthy subjects, the renal clearance of NO metabolite was measured. The metabolism ex vivo was evaluated by direct incubation of nitrite, the NO oxidation product, in blood from healthy humans. During inhalation of NO, the plasma levels of nitrate increased progressively, both in the healthy subjects (from 26 to 38 mumol/L, P < .001) and in the patients (from 72 to 90 mumol/L, P < .001). Methemoglobin (MetHb) also increased in the healthy subjects (from 7 to 13 mumol/L, P < .001) as well as in the patients (from 19 to 42 mumol/L, P < .01). No change in nitrosohemoglobin (HbNO) was detected, either in the healthy subjects or in the patients. In arterialized blood (O2 saturation, 94% to 99%), incubated nitrite was semiquantitatively converted to nitrate and MetHb. In venous blood (O2 saturation, 36% to 85%) moderate amounts of HbNO were also formed. Plasma and urinary clearance of nitrate in healthy subjects averaged 20 mL/min. We conclude that uptake into the red blood cells with subsequent conversion to nitrate and MetHb is a major metabolic pathway for endogenously formed NO. Nitrate may then enter the plasma to be eliminated via the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhalation of nitric oxide in acute lung injury: results of a European multicentre study

Objective: To determine whether inhalation of nitric oxide (INO) can increase the frequency of reversal of acute lung injury (ALI) in nitric oxide (NO) responders. Design: Prospective, open, randomised, multicentre, parallel group phase III trial. Setting: General ICUs in 43 university and regional hospitals in Europe. Patients: Two hundred and sixty-eight adult patients with early ALI. Interventions: NO responders were patients whose PaO2 increased by more than 20 % when receiving 0, 2, 10 and 40 ppm of INO for 10 min within 96 h of study entry. Responders were randomly allocated to conventional treatment with or without INO. INO, 1–40 ppm, was given at the lowest effective dose for up to 30 days or until an end point was reached. The primary end point was reversal of ALI. Clinical outcome parameters and safety were assessed in all patients. Results: Two hundred and sixty-eight patients were recruited, of which 180 were randomised NO responders. Frequency of reversal of ALI was no different in INO patients (61 %) and controls (54 %; p > 0.2). Development of severe respiratory failure was lower in the INO (2.2 % ) than controls (10.3 %; p < 0.05). The mortality at 30 days was 44 % for INO patients, 40 % for control patients (p > 0.2 vs INO) and 45 % in non-responders. Conclusions: Improvement of oxygenation by INO did not increase the frequency of reversal of ALI. Use of inhaled NO in early ALI did not alter mortality although it did reduce the frequency of severe respiratory failure in patients developing severe hypoxaemia.

Thoracic Epidural Anesthesia During Coronary Artery Bypass Surgery: Effects on Cardiac Sympathetic Activity, Myocardial Blood Flow and Metabolism, and Central Hemodynamics

The effects of high thoracic epidural anesthesia (TEA) on cardiac sympathetic nerve activity, myocardial blood flow and metabolism, and central hemodynamics were studied in 20 patients undergoing coronary artery bypass grafting (CABG). In 10 of the patients, TEA (T1-5 block) was used as an adjunct to a standardized fentanyl-nitrous oxide anesthesia. Hemodynamic measurements and blood sampling were performed after induction of anesthesia but prior to skin incision and after sternotomy. Assessment of total and cardiac sympathetic activity was performed by means of the norepinephrine kinetic approach. Prior to surgery, mean arterial pressure (MAP), great cardiac vein flow (GCVF), and regional myocardial oxygen consumption (Reg-MVO2) were lower in the TEA group compared to the control group. During sternotomy there was a pronounced increase in cardiac norepinephrine spillover, MAP, systemic vascular resistance index (SVRI), pulmonary capillary wedge pressure (PCWP), GCVF, and Reg-MVO2 in the control group. These changes were clearly attenuated in the TEA group. None of the patients in the TEA group had metabolic (lactate) or electrocardiographic signs of myocardial ischemia. Three patients in the control group had indices of myocardial ischemia prior to and/or during surgery. We conclude that TEA attenuates the surgically mediated sympathetic stress response to sternotomy, thereby preventing the increase in myocardial oxygen demand in the pre-bypass period without jeopardizing myocardial perfusion.

Positive end-expiratory pressure optimization using electric impedance tomography in morbidly obese patients during laparoscopic gastric bypass surgery.

Background:  Morbidly obese patients have an increased risk for peri‐operative lung complications and develop a decrease in functional residual capacity (FRC). Electric impedance tomography (EIT) can be used for continuous, fast‐response measurement of lung volume changes. This method was used to optimize positive end‐expiratory pressure (PEEP) to maintain FRC.

Estimation of functional residual capacity at the bedside using standard monitoring equipment: a modified nitrogen washout/washin technique requiring a small change of the inspired oxygen fraction.

We developed a modified nitrogen washin/washout technique based on standard monitors using inspiratory and end-tidal gas concentration values for functional residual capacity (FRC) measurements in patients with acute respiratory failure (ARF). For validation we used an oxygen-consuming lung model ventilated with an inspiratory oxygen fraction (Fio2) between 0.3 and 1.0. The respiratory quotient of the lung model was varied between 0.7 and 1.0. Measurements were performed changing Fio2 with fractions of 0.1, 0.2, and 0.3. In 28 patients with ARF, duplicate measurements were performed. In the lung model, an Fio2 change of 0.1 resulted in a value of 103 ± 5% of the reference FRC value of the lung model, and the precision was equally good up to an Fio2 of 1.0 with a value of 103 ± 7%. In the patients, duplicate measurements showed a bias of −5 mL with a 95% confidence interval [−38; 29 mL ]. A comparison of a change in Fio2 of 0.1 with 0.3 showed a bias of −9 mL and limits of agreement of [−365; 347 mL]. This study shows good precision of FRC measurements with standard monitors using a change in Fio2 of only 0.1. Measurements can be performed with equal precision up to an Fio2 of 1.0.

Increase in survival and bystander CPR in out-of-hospital shockable arrhythmia: bystander CPR and female gender are predictors of improved outcome. Experiences from Sweden in an 18-year perspective

Objectives In a national perspective, to describe survival among patients found in ventricular fibrillation or pulseless ventricular tachycardia witnessed by a bystander and with a presumed cardiac aetiology and answer two principal questions: (1) what are the changes over time? and (2) which are the factors of importance? Design Observational register study. Setting Sweden. Patients All patients included in the Swedish Out of Hospital Cardiac Arrest Register between 1 January 1990 and 31 December 2009 who were found in bystander-witnessed ventricular fibrillation with a presumed cardiac aetiology. Interventions Bystander cardiopulmonary resuscitation (CPR) and defibrillation. Main outcome measures Survival to 1 month. Results In all, 7187 patients fulfilled the set criteria. Age, place of out-of-hospital cardiac arrest (OHCA) and gender did not change. Bystander CPR increased from 46% to 73%; 95% CI for OR 1.060 to 1.081 per year. The median delay from collapse to defibrillation increased from 12 min to 14 min (p for trend 0.0004). Early survival increased from 28% to 45% (95% CI 1.044 to 1.065) and survival to 1 month increased from 12% to 23% (95% CI 1.058 to 1.086). Strong predictors of early and late survival were a short interval from collapse to defibrillation, bystander CPR, female gender and OHCA outside the home. Conclusion In a long-term perspective in Sweden, survival to 1 month after ventricular fibrillation almost doubled. This was associated with a marked increase in bystander CPR. Strong predictors of outcome were a short delay to defibrillation, bystander CPR, female gender and place of collapse.

Conversion of inhaled nitric oxide to nitrate in man

1 Nitric oxide (NO) is potentially useful as a selective vasodilator drug in infants and adults with pulmonary hypertension. In vitro and in vivo observations demonstrate that NO may be converted to nitrate in the blood, to be further excreted into the urine. The aim of the present study was to assess quantitatively the importance of this pathway for inhaled NO in human subjects. 2 Healthy subjects inhaled 15NO (25 p.p.m.) for 1 h. The plasma and urine levels of 15NO3‐ were followed for 2 and 48 h, respectively. 3 The measured retention of 15NO in the lungs was 224 ± 13 μmol, corresponding to 90 ± 2% of the inhaled amount. Plasma 15NO3‐ increased during the inhalation of 15NO, to about 15μmoll_1, and fell when inhalation of 15NO was terminated. 4 Urinary excretion of 15NO3‐ during the first 24 h after inhalation was 154 ± 12μmol. During the following 24 h another 8 ± 2 μmol of 15NO3 appeared in the urine. 5 We conclude that conversion of inhaled NO to nitrate is a major metabolic pathway in man, covering more than 70% of its inactivation. The metabolic fate of the remaining NO inhaled requires further study.

Clinical evaluation of a partial CO2 rebreathing technique for cardiac output monitoring in critically ill patients

Background: Monitoring central hemodynamics is essential in critically ill patients and less invasive techniques are needed. In this study, the clinical and technical performance of a new non‐invasive cardiac output monitor (NICO) based on partial CO2 rebreathing technique and a modified Fick equation were evaluated. The various sources of possible errors in measurement of cardiac output (CO), carbon dioxide production (V˙CO2) and pulmonary shunt were also assessed.

Warning! Suctioning. A lung model evaluation of closed suctioning systems

Background: Closed system suctioning, CSS, has been advocated to avoid alveolar collapse. However, ventilator manufacturers indicate that extreme negative pressure levels can be obtained during closed system suctioning, impeding the performance of the ventilator.

Direct Measurement of Intratracheal Pressure in Pediatric Respiratory Monitoring

We describe a method based on a Fabry-Perot interferometer at the tip of an optic fiber with a diameter of 0.25 mm for direct measurement of tracheal pressure in pediatric respiratory monitoring. The response time of the pressure transducer and its influence on the resistance of pediatric endotracheal tubes (internal diameter, 2.5 to 5 mm) during constant and dynamic flow at different ventilator settings in a lung model were measured. The transducer was positioned at −1.5 (inside), 0, and +1.5 cm (outside) relative to the tip of the endotracheal tube and compared with a reference pressure inside the trachea. The clinical application of the transducer was tested in five pediatric patients. The response time of the transducer was 1.3 ms. The influence of the fiberoptic transducer on tube resistance was negligible during constant flow in inspiratory and expiratory directions for all endotracheal tubes tested. There was no difference in pressure measurements with the transducer positioned at or 1.5 cm below or above the tip of the endotracheal tube during dynamic measurements. During clinical circumstances insertion of the fiberoptic transducer was easy, recordings were stable, and the safety of the patient was not jeopardized. The fiberoptic transducer provided a reliable and promising way of monitoring tracheal pressure in intubated pediatric patients. The presence of the probe did not interfere with either pressure-flow relationship or patient care and safety. The technique is proposed for monitoring of respiratory mechanics and calculation of changes in tube resistance caused by kinking and secretions.