*3.4.3 NOHb*

Nakajima and Oda have shown that the NOHb concentration is 0.13% in the blood during 20 min of 10 ppm NO inhalation [56]. This low concentration suggests the rapid turnover of NOHb, in which NOHb is presumably an intermediate in the conversion from NO to NO2 − and NO3 −.

#### *3.4.4 Conversion of NO2 − to NO3 −*

When 5 mM NO2 − is added to human blood, NO3 − changes are detected within 10 min [57]. The intravenous injection of sodium nitrite to rabbits results in the rapid disappearance of NO2 −. After the intratracheal injection of 13NO2 −, 70% of 13NO2 − changed to 13NO3 −, and 26% remained as 13NO2 − [58]. These observations suggest that NO2 − is converted to NO3 − in red blood cells [59]. NO2 − and NO3 − are stable and unchanged in plasma without red blood cells.

#### **Figure 6.**

*Reaction of NO with Hb. NO reacts with Fe2+ of oxy-Hb making MetHb and NO3 − and combines with deoxy-Hb making NOHb. NOHb reacts with O2 making MetHb and NO3 −.*

**75**

**Figure 7.**

*Metabolic fate of NO. Almost all inhaled NO is converted to NO3*

*urine; 10% is changed to nitrogen compound except NO3*

*and discharged outside of the body.*

*Endogenous and Inhaled Nitric Oxide for the Treatment of Pulmonary Hypertension*

A clear understanding of the fate of iNO is critical for its clinical use in humans.

− → NO2

− → N2 by stomach flora.

*−. Forty-five percent of NO3*

*− and excreted in feces; 10% is changed to*

*− and NO2*

*urea through the digestive tract and liver and excreted in urine. The rest will be changed to N2 in the stomach*

*− is excreted in*

As previously mentioned, the metabolic fate of iNO was examined in the early 1980s, and it was found that retention of iNO in the body was lacking (**Figure 7**). An inhalation study of 15NO in rats investigated the metabolism of iNO. In the carcasses, 1.6% of total inhaled 15N was detected, similar to the level of natural 15N. This result suggests that iNO largely does not remain in the body. About 55% of total inhaled 15N was recovered in urine [41, 42], including 45% as nitrates and 10% as urea (**Figure 7**). About 10% of total inhaled 15N was recovered as undetermined nitrogen compounds in feces. The remaining 35% was not recovered but is assumed

During cardiopulmonary bypass(CPB), hemolysis causes an increase in Hb plasma concentration due to the destruction of red blood cells. Hb includes oxy-Hb and deoxy-Hb. Oxy-Hb causes vasoconstriction, which is partly due to the depletion of NO available to induce vascular smooth muscle relaxation. NO is produced in and released from endothelial cells, some of which reaches adjacent vascular smooth muscles, causing vasorelaxation, and some of which diffuses into the plasma. If the amount of oxy-Hb in the plasma increases, the binding of NO to oxy-Hb increases, resulting in less NO reaching adjacent smooth muscle cells. Thus, the presence of large amounts of oxy-Hb might decrease NO availability in vascular smooth muscle

*DOI: http://dx.doi.org/10.5772/intechopen.89381*

to be N2 produced from the reduction of NO3

**3.5 iNO effects in remote organs**

cells (**Figure 8**).

*3.4.5 No retention of iNO in the body*

*Endogenous and Inhaled Nitric Oxide for the Treatment of Pulmonary Hypertension DOI: http://dx.doi.org/10.5772/intechopen.89381*

#### *3.4.5 No retention of iNO in the body*

A clear understanding of the fate of iNO is critical for its clinical use in humans. As previously mentioned, the metabolic fate of iNO was examined in the early 1980s, and it was found that retention of iNO in the body was lacking (**Figure 7**).

An inhalation study of 15NO in rats investigated the metabolism of iNO. In the carcasses, 1.6% of total inhaled 15N was detected, similar to the level of natural 15N. This result suggests that iNO largely does not remain in the body. About 55% of total inhaled 15N was recovered in urine [41, 42], including 45% as nitrates and 10% as urea (**Figure 7**). About 10% of total inhaled 15N was recovered as undetermined nitrogen compounds in feces. The remaining 35% was not recovered but is assumed to be N2 produced from the reduction of NO3 − → NO2 − → N2 by stomach flora.

#### **3.5 iNO effects in remote organs**

During cardiopulmonary bypass(CPB), hemolysis causes an increase in Hb plasma concentration due to the destruction of red blood cells. Hb includes oxy-Hb and deoxy-Hb. Oxy-Hb causes vasoconstriction, which is partly due to the depletion of NO available to induce vascular smooth muscle relaxation. NO is produced in and released from endothelial cells, some of which reaches adjacent vascular smooth muscles, causing vasorelaxation, and some of which diffuses into the plasma. If the amount of oxy-Hb in the plasma increases, the binding of NO to oxy-Hb increases, resulting in less NO reaching adjacent smooth muscle cells. Thus, the presence of large amounts of oxy-Hb might decrease NO availability in vascular smooth muscle cells (**Figure 8**).

#### **Figure 7.**

*Metabolic fate of NO. Almost all inhaled NO is converted to NO3 −. Forty-five percent of NO3 − is excreted in urine; 10% is changed to nitrogen compound except NO3 − and NO2 − and excreted in feces; 10% is changed to urea through the digestive tract and liver and excreted in urine. The rest will be changed to N2 in the stomach and discharged outside of the body.*

#### **Figure 8.**

*NO formed in the endothelium is scavenged by plasma oxygenated Hb. (A) NO produced in the endothelium diffuses into adjacent smooth muscle cells and binds with guanylate cyclase. (B) If O2Hb (Fe2+) increases, NO produced in the endothelium diffuses into the blood and scavenged by O2Hb (Fe2+), decreasing the amount of NO diffused into smooth muscle cells. (C) If O2 Hb(Fe2+) is converted to MetHb(Fe3+) by NO inhalation, NO is not scavenged, which recovers the amount of NO diffusing to the smooth muscle side.*

Acute kidney injury is a common complication after cardiac surgery with prolonged CPB. Because oxygen tension is high during CPB, plasma oxy-Hb exhibits substantial hemolysis, causing vasoconstriction in the kidney. Recently, NO was demonstrated to decrease the occurrence of acute kidney injury and chronic kidney disease 1 year postoperatively [47]. NO inhalation at 80 ppm was started at the onset of CPB via a CPB machine and was continued after CPB via a mechanical ventilator for 24 h or less if patients were ready to be extubated early. Under NO inhalation, oxy-Hb was converted to MetHb, which recovered NO availability to vascular smooth muscle cells due to the decrease in oxy-Hb. Thus, exogenous NO inhalation might increase endogenous NO availability to counteract renal vasoconstriction during CPB.

In brief, the reduction of nitrite and nitrate produces NO (**Figure 9**). Nitrite is reduced by deoxy-Hb, respiratory chain enzymes, xanthine oxidoreductase, deoxygenated myoglobin, and protons, facilitating the transfer of protons to NO2 − and thereby producing NO. These reactions are intensified under acidic and hypoxic states. After iNO is converted to NO2 − and NO3 −, NO can be recycled from nitrite and used to protect organs from ischemia-reperfusion injury [48, 51].

In liver transplantation, the inhalation of 80 ppm NO until reperfusion ameliorates apoptosis, attenuated increases of liver enzymes, and enhanced the recovery of coagulation factors [48].

In orthopedic knee surgery, NO inhalation prevented increases in the adhesion molecule expression on granulocytes, plasma selectin levels, and NF-κB expression in quadriceps muscles [51]. NO inhalation was started before the tourniquet application and was continued during reperfusion until the completion of surgery.

**77**

*Endogenous and Inhaled Nitric Oxide for the Treatment of Pulmonary Hypertension*

**4. Update on the clinical application of iNO in pediatric patients**

*relation. Please count the number of O before and after the reduction responses.*

PAH or operability for children with congenital heart disease.

**premature newborns**

*), and cytochrome enzymes (Fe2+). NO2*

**Figure 9.**

*(H+*

**4.1 Role of inhaled NO in the prevention of bronchopulmonary dysplasia in**

Bronchopulmonary dysplasia (BPD), which is characterized by impaired pulmonary development resulting from insults affecting the immature lung, including inflammation, hyperoxia, and mechanical ventilation, is associated with high mortality and adverse long-term neurological and respiratory outcomes in infants born very preterm. Although the effectiveness of iNO for the treatment of PPHN is largely due to its function as a selective pulmonary vasodilator, laboratory observations also suggest other important biological effects of NO, such as roles in decreasing lung inflammation (e.g., lung vascular protein leak; pulmonary neutrophil accumulation) [61], reducing oxidant stress [62], decreasing pulmonary vascular cell proliferation [63], and enhancing alveolarization and lung growth [64–66]. These observations have led to investigations into the use of iNO to prevent the development of BPD in premature newborns. In an initial randomized,

After NO was identified as an endothelial cell-derived relaxation factor and following preclinical studies, iNO therapy has been studied extensively in multicenter randomized trials as well as in early pilot studies of infants with severe hypoxemia associated with PH or infants with congenital diaphragmatic hernia (CDH) [60]. These studies have demonstrated improved oxygenation and reduction in the need for extracorporeal membrane oxygenation (ECMO) therapy, leading to the approval of iNO therapy by the Food and Drug Administration for use in patients at >34-week gestation with hypoxemic respiratory failure and persistent PH of the newborn (PPHN). Over the last two decades, the discussion of its application has been extended to premature infants and acute pulmonary vascular response testing to assess indications for specific pulmonary vasodilator therapy for patients with

*Recycle of NO from nitrite and nitrate. Nitrate is reduced to nitrite, and subsequent reduction of nitrite forms NO. Reducing substances are deoxy-Hb [Hb(Fe2+)], myoglobin [Mb(Fe2+)], xanthine oxidase, hydrogen ion*

*− is reduced by deoxy-Hb(Fe2+) to NO showing stoichiometric*

*DOI: http://dx.doi.org/10.5772/intechopen.89381*

*Endogenous and Inhaled Nitric Oxide for the Treatment of Pulmonary Hypertension DOI: http://dx.doi.org/10.5772/intechopen.89381*

#### **Figure 9.**

*Recycle of NO from nitrite and nitrate. Nitrate is reduced to nitrite, and subsequent reduction of nitrite forms NO. Reducing substances are deoxy-Hb [Hb(Fe2+)], myoglobin [Mb(Fe2+)], xanthine oxidase, hydrogen ion (H+ ), and cytochrome enzymes (Fe2+). NO2 − is reduced by deoxy-Hb(Fe2+) to NO showing stoichiometric relation. Please count the number of O before and after the reduction responses.*


*2.4. Estimation of Photovoltaic Power: Artificial Neural Network Model*

The ANN models used in this study are multi-layer perceptrons, a class of neural networks composed of multiple layers of interconnected artificial neurons. The first is the input layer, which ingests the different input variables fed into the neural network model. The last is known as the output layer, which yields the predicted values generated by the model. Between these two layers, there is a variable number of hidden layers (zero or more) which connect the input and output layers. The number of artificial neurons in the output layer is determined by the number of output variables. However, the number of neurons for the input and hidden layers is not predetermined, but rather a variable parameter to be optimised.

All the different MLP models built for this study share a common set of configuration parameters. The neurons in both the input and hidden layers use the rectifier linear unit (ReLU) function as the activation function [28]. Batch learning is used as the training methodology [29]. The chosen optimisation algorithm is Adaptive Moment Estimation (Adam), a stochastic gradient descent method [30]. The training stop criterion uses a separated fraction of the training data (a randomly chosen 10% of the training hours) to evaluate the current stage of the trained model, using the mean absolute error (MAE) metric shown below. An additional patience-based stop criterion is included, where training stops if the performance of the model does not improve for 100 consecutive epochs.

$$MAE = \sum\_{i=1}^{N} \frac{|X\_i - Y\_i|}{N} \tag{1}$$

In the next subsections, the monitoring and GDAS datasets are combined into three different scenarios to train and test the different MLP models. At the same time, the available days of data are split into training and testing samples. These samples, applied over the different scenarios, are used to select the best MLP model and to evaluate its performance when fed with monitoring and/or GDAS meteorological data.


**9. The Use of Growth Promoters in MoS2 Synthesis**

The growth of 2D layers is driven by the chemical potentials and surface energies of the material and substrate. Depending on the balance between adhesion to the surface of atoms and adatom cohesive force, 2D layer growth might be favoured with respect to island nucleation. If the surface adhesion is insufficient to allow layer growth, the use of additional molecules (that are not involved in the chemical processes underlying the growth) is an attractive method to obtain 2D layers. These elements are generally known as "promoters", and their use has been proven to be very beneficial for many aspects of the growth of MoS2.

The inclusion of other elements that may favour the nucleation and lateral growth of 2D layers was recognized as crucial in the very early steps of the research on the CVD growth of this material. In particular, the pioneering work of Ling et al. [85] analysed many possible options for promoters, giving an ample view of the possibilities; this was a fundamental paper to have a wide insight on many possible substances to be used as promoters. We limit our discussion to the most successful and useful promoters reported so far, to allow the reader a general view of the state of the art on this topic (Table 1). Many approaches have been proposed in these years, and we consider it useful to divide growth promoters into two main categories: inorganic solid state and organic. A section on the effect of surface treatments is also included, as this is another important element in determining the quality of the grown 2D layers.

From the point of view of understanding the mechanisms underlying the effects of promoters, theoretical work is currently underway, with different proposals to be investigated. For example, in [86], the effect of alkali metal compounds as promoters was studied, and the authors provided an explanation based on eutectic intermediates containing alkali metal molybdates and molybdenum oxides. Because of their low melting point, their mobility was enhanced in comparison with that of other molybdenum compounds, reducing the nucleation of new nanoislands and favouring lateral growth of existing ones.

**Table 1.** Growth promoters for the synthesis of MoS2 .

**Table 1.** *Cont.*


**4. Discussion**

Evaluating the value of health care is of paramount importance to keep improving patients' quality of life and optimizing associated costs. Hospitals' digitalization is still ongoing and offers a great potential for patients' evaluation along their entire care path. Beyond this, the real challenge that often arises in VBHC discussions is the absence of external benchmarks which compels us to compare our results within our institution or at different time intervals. The authors of the present study therefore created a new value-based dashboard for TSA, which allows an objective comparison with standard references.

According to our results, 78% of the TSAs performed at our institution offered a substantial value to patients. It is worth noting that 41 patients (35%) had a substantial delivered value although they had either a quality of care below the expectations or an excessive direct cost (Figure 2). This emphasizes the importance of evaluating both indicators together rather than interpreting them independently from each other.

Different authors recently evaluated the value delivered by TSA at short term using different methods [12–14]. Menendez et al. [14] defined the delivered value as the postoperative ASES score divided by the hospitalization time-driven activity-based costs. More comparable to our value calculation method, Berglund et al. [13] divided the ratio of PROM improvement (in units of MCID) by the total hospitalization cost. Both aforementioned studies found that reverse TSA was associated with a decreased delivered value compared to anatomic TSA, which corroborates our findings. Although it was expected given that reverse TSA has a higher cost associated with the management of rotator cuff deficiencies, it is important to note that such an association can be reversed at some point since different studies already revealed mid- or long-term concerns on anatomic TSA (glenoid loosening, difficult revision procedures, and disappointing outcomes) [15–17]. Furthermore, the indications for these two procedures can be different and further analyses with matched cohorts are needed [18].

In our study, the delivered value was higher for shoulders with a lower preoperative function or higher pre-operative pain since greatest clinical improvements are usually observed for patients with worse preoperative health [19]. Our analyses also revealed that current or former smokers had a lower delivered value compared to non-smokers. The negative impact of tobacco use on outcomes after TSA is well reported [20–23] and emphasizes smoking cessation programs [24]. In the next decades, machine learning algorithms might be able to accurately predict postoperative patient outcomes based on their preoperative characteristics [25]. Such prognostic tools would help manage patient expectations [26] and avoid surgery for patients who would not benefit from it, thereby reducing associated risks for the patients while lowering costs for the health care system.

Different authors already worked on the creation of VBHC dashboards/scorecards [2,27]. Riley et al. published an innovative method to illustrate patient value following total hip and knee arthroplasties [2]. This method consisted of comparing the results of different surgeons within the same institution, which motivates them to outperform for the sake of their patients. However, the use of internal references such as orthopedic department averages for direct costs or PROMs can be misleading. For instance, implementing this method in small institutions where only one surgeon works in a specific medical field would be unwarranted. Furthermore, this method could reveal outstanding results for a surgeon even though the entire department has bad outcomes. In our study, we proposed to use SCB thresholds for the interpretation of PROMs improvements and to estimate the direct cost reference by using the DRG-based standard reimbursement system. The proposed dashboard can guide toward patient value improvement before a new methodology and strong external benchmarks using data from several hospitals are created.

Continuous improvements based on measuring the own performance in order to provide the best possible value to customers has been a key success factor for successful companies across all industries. VBHC is bringing this principle into health care, to the great benefit of patients and the system. The mentality of the different health care players is changing, and the competition slowly shifts from micro-costing only to patient outcome and cost optimization. It is setting the stage for a new way of thinking, collaborating, and competing, thereby opening new opportunities to reinforce excellence in care. The combination of medical expertise with an open mindset for change and self-evaluation is essential. In this sense, VBHC is redefining the basis of what leadership is for healthcare professionals. An essential development will be the emergence of new reimbursement models rewarding better outcomes. This will again require a fundamental change in people's mindset, while providing a great opportunity for early adopters to accelerate change.

Our study has several limitations. First, our analyses only illustrate the delivered patient value at short follow-up. Furthermore, patients for whom complications were noted might have been double-penalized since such clinical outcomes might also affect PROMs. To reduce the aforementioned bias, an artificial floor was used for patients who had a negative change in PROMs. Second, the weighting of clinical outcomes was solely based on the senior surgeon's experience. The logic was to attribute an equal weight (0.2) to the five principal outcomes that are crucial for shoulder arthroplasty success: global function (ASES and Constant scores), pain, complication (intra- or post-operatively), PJI, and revision. If a principal outcome comprised different sub-outcomes (e.g., Global function), the weight was then split proportionally to have a similar weighting between sub-outcomes (e.g., 0.1 for the ASES score and 0.1 for the Constant score). A Delphi method engaging the patients, insurance providers, and other key important players would have been more appropriate. Third, our outcome and cost indicators were not risk-adjusted, which can represent a bias if comparisons are made between two surgeons with differences in case mix and patient populations. Fourth, the direct cost reference was estimated to be 44% of the standard TSA reimbursement based on our patients with basic insurance only. A thorough analysis of the DRG-based standard reimbursement system should be performed and published so that each institution knows the theoretical amount supposed to cover direct costs. Fifth, the MCID and SCB values might change across different patient populations. Lastly, a broader analysis focusing on a specific pathology (e.g., glenohumeral arthritis) rather than on a particular treatment (e.g., TSA) would be more in line the VBHC concept.