Comparing in vitro nitric oxide blood uptake to its pulmonary diffusing capacity.

Whether endothelium derived Nitric Oxide (NO) uptake by the blood is limited by a boundary layer, the red cell membrane or its interior is the subject of continued debate. Whether lung uptake of NO in the single-breath DLNO test is limited by blood or not is also debated. To understand which processes are limiting blood NO uptake we have modelled NO chemical kinetics and we have derived a shrinking core model, Thiele Modulus and FTCS (Euler) numerical solution. In a rapid reaction apparatus, NO uptake appears limited by a boundary layer, and throughout the red cell, by diffusion. In the single breath situation, and arguably with endogenous NO in vivo, NO uptake appears limited by a boundary layer and a pseudo first order chemical reaction in the outer molecular layers of the red cell. We have not found evidence to support red cell membrane limitation.

Lung Diffusing Capacities (DL ) for Nitric Oxide (NO) and Carbon Monoxide (CO): The Evolving Story.

Nitric oxide and carbon monoxide diffusing capacities (DLNO and DLCO ) obey Fick's First Law of Diffusion and the basic principles of chemical kinetic theory. NO gas transfer is dominated by membrane diffusion (DM ), whereas CO transfer is limited by diffusion plus chemical reaction within the red cell. Marie Krogh, who pioneered the single-breath measurement of DLCO in 1915, believed that the combination of CO with red cell hemoglobin (Hb) was instantaneous. Roughton and colleagues subsequently showed, in vitro, that the reaction rate was finite, and prolonged in the presence of high P O 2 . Roughton and Forster (R-F) proposed that the resistance to transfer (1/DL ) was the sum of the membrane resistance (1/DM ) and (1/θVc), the red cell resistance (θ being the CO or NO conductance for blood uptake and Vc the capillary volume). From this R-F equation, DM for CO and Vc can be solved with simultaneous NO and CO inhalation. At near maximum exercise, DMCO and Vc for normal subjects were 88% and 79%, respectively, of morphometric values. The validity of these calculations depends on the values chosen for θ for CO and NO, and on the diffusivity of NO versus CO. Recent mathematical modeling suggests that θ for NO is "effectively" infinite because NO reacts only with Hb in the outer 0.1 µM of the red cell. An "infinite θNO " recalculation reduced DMCO to 53% and increased Vc to 95% of morphometric values. © 2020 American Physiological Society. Compr Physiol 10:73-97, 2020.

Permeability and diffusivity of nitric oxide in human plasma and red cells.

A simple diffusion cell was made to measure the permeability and diffusivity of Nitric Oxide in human plasma and red cells. Nitric oxide was passed through the cell containing plasma or nitrited red cells enclosed by silicone membranes. Steady state permeability (αNODNO ) was calculated from the cell dimensions and from the NO bulk flow entering and leaving the cell. The diffusion coefficient (DNO) was calculated in three ways: (i) by dividing the steady state permeability by published values for solubility (αNO ) in water at 26 °C and 37 °C (ii) by a numerical method and (iii) by an analytical method. Mean steady state permeability (95% confidence intervals) were plasma (26 °C) 5.57 × 10-11 (2.35 × 10-11-1.32 × 10-10) and (37 °C) 5.48 × 10-11 (2.13 × 10-11-1.41 × 10-10) mol cm-1 s-1 atm-1 and red cells (26 °C) 6.74 × 10-12 (1.29 × 10-12-3.53 × 10-11) and (37 °C) 3.93 × 10-11 (1.39 × 10-11-1.11.10-10) mol cm-1 s-1 atm-1. Median Diffusion Coefficients (DNO) for plasma at 37 °C ranged from 3-3.36 × 10-5 cm2 s-1 and red cells 2.41-2.94 × 10-5 cm2 s-1 depending on the method used. These values may be used for modelling NO transport in vivo in the human lung and capillary. Parameters used for modelling in vivo should be measured at 37 °C.

Hypothesis: Why θNO could be finite in vitro but infinite in vivo.

There is controversy as to whether the lung Diffusing Capacity for Nitric Oxide (DLNO) is a direct measure of DM in the Roughton-Forster equation or whether θNO is finite and DM is greater than DLNO. Despite in vitro evidence that θNO is finite, some groups believe that it is infinite in vivo and that DMNO/DMCO (α) is greater than predicted by the combined Fick/Graham law of Gas Diffusion through a membrane. We here present a hypothesis applying the fundamental rules of combined diffusion and chemical reaction to a red cell to explain (i) why θNO could be finite in vitro but effectively infinite in vivo and (ii) why ∝ could appear greater than predicted. DLNO would mainly reflect the conductance of the alveolar capillary membrane with a smaller contribution from plasma and minimal contribution from the outermost layers of the red cell. If this hypothesis is correct DMCO and Vc could not be obtained from a combined DLNO and DLCO manoeuvre since these variables would differ for NO and for CO.

The blood transfer conductance for CO and NO.

Nitric oxide was introduced over 30 years ago as a test gas for alveolar capillary diffusion. As for CO its transfer has been interpreted according to the Roughton Forster relationship: 1/DL=1/DM+1/θVc. There has been disagreement, since the first measurements of DLNO, over whether θNO is infinite and thus DLNO=DMNO. There is overwhelming in vitro evidence that θNO is finite yet several groups (Coffman et al., 2017; Tamhane et al., 2001) use an infinite value in vivo. They also assume that DMNO is greater than twice DMCO, making DMCO less than that predicted by the physical laws of diffusion. Finally some (Coffman et al., 2017) recommend use of Reeve and Park's value for θCO (Reeves and Park, 1992; Coffman et al., 2017) rather than Forster's (Forster, 1987). Their grounds for doing so are that the combination of an infinite theta NO, an empirical value for DMNO/DMCO (>2.0) and Reeve and Park's θCO gives a value of DMCO (using a combined DLNO-DLCO analysis) which agrees with the DMCO value calculated separately by the classical two-stage oxygen technique of Roughton and Forster. In this paper we examine whether there are physiological reasons for assuming that DMNO is over twice DMCO in vivo. We are critical of Reeves and Park's estimate for the 1/θCO-PO2 relationship. We review in vitro estimates of θCO in the light of Guenard et al.'s recent in vivo estimate.

Standardisation and application of the single-breath determination of nitric oxide uptake in the lung.

Diffusing capacity of the lung for nitric oxide (DLNO), otherwise known as the transfer factor, was first measured in 1983. This document standardises the technique and application of single-breath DLNO This panel agrees that 1) pulmonary function systems should allow for mixing and measurement of both nitric oxide (NO) and carbon monoxide (CO) gases directly from an inspiratory reservoir just before use, with expired concentrations measured from an alveolar "collection" or continuously sampled via rapid gas analysers; 2) breath-hold time should be 10 s with chemiluminescence NO analysers, or 4-6 s to accommodate the smaller detection range of the NO electrochemical cell; 3) inspired NO and oxygen concentrations should be 40-60 ppm and close to 21%, respectively; 4) the alveolar oxygen tension (PAO2 ) should be measured by sampling the expired gas; 5) a finite specific conductance in the blood for NO (θNO) should be assumed as 4.5 mL·min-1·mmHg-1·mL-1 of blood; 6) the equation for 1/θCO should be (0.0062·PAO2 +1.16)·(ideal haemoglobin/measured haemoglobin) based on breath-holding PAO2 and adjusted to an average haemoglobin concentration (male 14.6 g·dL-1, female 13.4 g·dL-1); 7) a membrane diffusing capacity ratio (DMNO/DMCO) should be 1.97, based on tissue diffusivity.

The history of the pulmonary diffusing capacity for nitric oxide DL,NO.

The DL,NO (TL,NO) had its unexpected origins in the Paris "events" of 1968 and the unsuccessful efforts of the UK tobacco industry in the 1970's to create a "safer cigarette". Adoption of the technique has been slow due to the instability of NO in air, lack of standardisation of the technique and lack of agreement as to whether DL,NO is equal to or merely reflects membrane diffusing capacity (DM). With the availability of inexpensive analysers, standardisation of the technique and publication of reference equations we believe that its worldwide use will increase.

The significant blood resistance to lung nitric oxide transfer lies within the red cell.

The lung nitric oxide (NO) diffusing capacity (DlNO) mainly reflects alveolar-capillary membrane conductance (Dm). However, blood resistance has been shown in vitro and in vivo. To explore whether this resistance lies in the plasma, the red blood cell (RBC) membrane, or in the RBC interior, we measured the NO diffusing capacity (Dno) in a membrane oxygenator circuit containing ∼1 liter of horse or human blood exposed to 14 parts per million NO under physiological conditions on 7 separate days. We compared results across a 1,000-fold change in extracellular diffusivity using dextrans, plasma, and physiological salt solution. We halved RBC surface area by comparing horse and human RBCs. We altered the diffusive resistance of the RBC interior by adding sodium nitrite converting oxyhemoglobin to methemoglobin. Neither increased viscosity nor reduced RBC size reduced Dno. Adding sodium nitrite increased methemoglobin and was associated with a steady fall in Dno (P < 0.001). Similar results were obtained at NO concentrations found in vivo. The RBC interior appears to be the site of the blood resistance.

Improving Compliance with NICE Guidelines on Parkinson's isease: A Quality Improvement Study.

Parkinson's disease can progressively affect daily function and multidisciplinary teamwork is essential to provide high quality care. The National Institute of Health and Clinical Excellence (NICE) issued guidelines regarding diagnosis, follow-up, and multidisciplinary care. This quality improvement project sought to measure and improve the compliance of service provision against the guidelines. In total, 3 audit cycles were completed. Each audit involved reviewing notes of patients attending a Parkinson's disease outpatient clinic against the PD NICE guidelines audit criteria. The first and second audits showed compliance was high for the criteria relating to initial diagnosis and referral but poor for those criteria relating to multidisciplinary referral. A pro forma stamp was recommended to be placed in the notes at each regular Parkinson's outpatient review by a specified date (October 2009), with re-audit occurring in June 2011 as part of the official hospital audit plan. Compliance to the NICE criteria improved to 100% on all criteria measured. However, it was evident from the notes that the pro forma that had been recommended by the previous audit had been in use but was not at present. In fact the pro forma had been so successful that the clinicians had made each of the criteria a routine part of their consultations and so did not need to rely on it. Use of a checklist can have a lasting improvement on compliance with NICE guidelines, even if the intervention itself is transient.

Significant blood resistance to nitric oxide transfer in the lung.

Lung diffusing capacity for nitric oxide (DLNO) is used to measure alveolar membrane conductance (DMNO), but disagreement remains as to whether DMNO=DLNO, and whether blood conductance (thetaNO)=infinity. Our previous in vitro and in vivo studies suggested that thetaNO

Persistent orocutaneous and anal fistulae induced by nicorandil: a case report.

INTRODUCTION: Although nicorandil is prescribed widely, awareness of its potential to cause serious complications to the gastrointestinal tract mucosa is limited. Whilst nicorandil-induced oral and anal ulceration is well documented in the literature, nicorandil-induced fistulation is not. This is the first report in the literature of a single patient demonstrating simultaneous orocutaneous and anal fistulae during nicorandil therapy. Two separate cases of orocutaneous and anal fistulae associated nicorandil usage have previously been documented in specialist journals. CASE PRESENTATION: A 71-year-old Caucasian man presented with a 3-year history of concurrent orocutaneous and anal fistulae. He had been exposed to 30 mg twice-daily nicorandil therapy for 4 years. Both fistulae responded poorly to intensive and prolonged conventional treatment but healed promptly on reduction and eventual withdrawal of nicorandil therapy. CONCLUSION: Management of resistant cases of orocutaneous and anal fistulae in patients on high-dose nicorandil therapy may be impossible without reduction or even withdrawal of nicorandil.

A 47-year-old man with neuro-Sweet syndrome in association with Crohn's disease: a case report.

INTRODUCTION: Sweet's syndrome is a multi-system inflammatory disorder characterised by painful skin lesions and aseptic neutrophilic infiltration of various organs. We describe a case of Sweet's syndrome with aseptic meningitis in association with Crohn's disease (neuro-Sweet syndrome). This association has never been previously reported. CASE PRESENTATION: A 47-year-old Caucasian male with known Crohn's disease presented with headache, fever and skin lesions resembling erythema nodosum. The cerebrospinal fluid revealed leukocyte pleocytosis and dominant neutrophils, but cultures were negative. A skin biopsy revealed neutrophilic dermatosis compatible with Sweet's disease. The patient made a prompt recovery without the use of corticosteroids. CONCLUSION: Because of its multisystem nature, Sweet's syndrome may present diagnostic difficulty to specialists. Correct diagnosis by skin biopsy will prompt appropriate treatment.

Fatal Israeli spotted fever in a UK traveler to South Portugal.

A 63-year-old previously healthy woman developed a severe systemic infection 5 days after returning from a holiday to Southern Portugal. She subsequently died, and polymerase chain reaction of a blood sample was positive for Rickettsia conorii ssp israeliensis. The prevalence of severe forms of this illness in the Mediterranean Basin is discussed.

Femoral vein thrombophlebitis and septic pulmonary embolism due to a mixed anaerobic infection including Solobacterium moorei: a case report.

BACKGROUND: Primary foci of necrobacillosis infection outside the head and neck are uncommon but have been reported in the urogenital or gastrointestinal tracts. Reports of infection with Solobacterium moorei are rare. CASE PRESENTATION: A 37-year-old male intravenous drug user was admitted with pain in his right groin, fever, rigors and vomiting following a recent injection into the right femoral vein. Admission blood cultures grew Fusobacterium nucleatum, Solobacterium moorei and Bacteroides ureolyticus. The patient was successfully treated with intravenous penicillin and metronidazole. CONCLUSION: This case report describes an unusual case of femoral thrombophlebitis with septic pulmonary embolism associated with anaerobic organisms in a groin abscess. Solobacterium moorei, though rarely described, may also have clinically significant pathogenic potential.

Can a membrane oxygenator be a model for lung NO and CO transfer?

To model lung nitric oxide (NO) and carbon monoxide (CO) uptake, a membrane oxygenator circuit was primed with horse blood flowing at 2.5 l/min. Its gas channel was ventilated with 5 parts/million NO, 0.02% CO, and 22% O2 at 5 l/min. NO diffusing capacity (Dno) and CO diffusing capacity (Dco) were calculated from inlet and outlet gas concentrations and flow rates: Dno = 13.45 ml.min(-1).Torr(-1) (SD 5.84) and Dco = 1.22 ml.min(-1).Torr(-1) (SD 0.3). Dno and Dco increased (P = 0.002) with blood volume/surface area. 1/Dno (P < 0.001) and 1/Dco (P < 0.001) increased with 1/Hb. Dno (P = 0.01) and Dco (P = 0.004) fell with increasing gas flow. Dno but not Dco increased with hemolysis (P = 0.001), indicating Dno dependence on red cell diffusive resistance. The posthemolysis value for membrane diffusing capacity = 41 ml.min(-1).Torr(-1) is the true membrane diffusing capacity of the system. No change in Dno or Dco occurred with changing blood flow rate. 1/Dco increased (P = 0.009) with increasing Po2. Dno and Dco appear to be diffusion limited, and Dco reaction limited. In this apparatus, the red cell and plasma offer a significant barrier to NO but not CO diffusion. Applying the Roughton-Forster model yields similar specific transfer conductance of blood per milliliter for NO and CO to previous estimates. This approach allows alteration of membrane area/blood volume, blood flow, gas flow, oxygen tension, red cell integrity, and hematocrit (over a larger range than encountered clinically), while keeping other variables constant. Although structurally very different, it offers a functional model of lung NO and CO transfer.