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Table of Contents
Year : 2021  |  Volume : 24  |  Issue : 4  |  Page : 452-457
Inhaled nitric oxide before induction of anesthesia in patients with pulmonary hypertension

1 Department of Perioperative Medicine, CHU Gabriel Montpied, Clermont-Ferrand, France
2 Department of Perioperative Medicine, CHU Estaing, Clermont-Ferrand, France
3 Clinical Pharmacology Center (Inserm CIC 1405) CHU Clermont Ferrand, Clermont Ferrand, France
4 Biostatistics Unit, CHU Gabriel Montpied, Clermont-Ferrand, France
5 Centre Jean Perrin, Clermont-Ferrand, France
6 Department of Anesthesiology and Critical Care, Pitié-Salpêtrière Hospital, Sorbonne University, GRC 29, AP-HP, DMU DREAM, Paris, France

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Date of Submission16-Apr-2020
Date of Decision06-Aug-2020
Date of Acceptance18-Aug-2020
Date of Web Publication18-Oct-2021


Background: The aim of this study was to examine the action of inhaled nitric oxide in the patients with pulmonary hypertension administered with a face mask before anesthesia induction.
Methods: Ten adult patients scheduled for heart surgery with sternotomy were included in this prospective, interventional, single centre study. The inclusion criteria were patients scheduled for heart surgery with sternotomy with cardiopulmonary bypass (CPB), aged >18 years which presents a pulmonary hypertension (PH) (class 2 or 3 according to the Dana Point classification) with systolic pulmonary arterial pressure (PAPS) >40 mmHg diagnosed by preoperative right cardiac catheterization or by transthoracic echocardiography. The exclusion criteria were: heart transplant, PH of type 1, 4, 5, according to the Dana Point classification, methemoglobin reductase deficit, incapacity to understand the protocol and sign the consent.
Results: The administration of iNO decrease pulmonary hypertension (P < 0,001 compared to room air; P = 0,01 compared to pure oxygen administration). The iNO administration did not improve arterial blood oxygenation. The hyperoxia, decrease the cardiac index even with right ventricular post charge decrease. The increased blood oxygenation content cause systemic vascular vasoconstriction and decrease the peripheral oxygen extraction showed with VO2 linear increase (P < 0,001).
Conclusions: The administration of inhaled nitric oxide with a face mask before anaesthesia induction is safe and effective method to reduce pulmonary hypertension. The oxygen and hyperoxia influences the systemic vascular resistance and peripheral oxygen consumption.

Keywords: Anesthesia induction, inhaled nitric oxide, pulmonary hypertension

How to cite this article:
Eljezi V, Rochette L, Dualé C, Pereira B, Boby H, Constantin JM. Inhaled nitric oxide before induction of anesthesia in patients with pulmonary hypertension. Ann Card Anaesth 2021;24:452-7

How to cite this URL:
Eljezi V, Rochette L, Dualé C, Pereira B, Boby H, Constantin JM. Inhaled nitric oxide before induction of anesthesia in patients with pulmonary hypertension. Ann Card Anaesth [serial online] 2021 [cited 2022 Aug 12];24:452-7. Available from:

   Introduction Top

Pulmonary hypertension (PH) is a frequent pulmonary disease that represents an independent morbidity and mortality factor in patients who need surgery.[1],[2],[3],[4]

Perioperative morbidity represents 25–42% of PH patients,[5] thus accurate preoperative assessment and diligent anesthetic management are crucial for the best outcome.[1] The PH patients had a significantly increased risk for hemodynamic instability, heart failure, postoperative sepsis, and respiratory failure.[6] Acidosis, hypercapnia, hypoxemia, hypothermia, increased sympathetic activity, and arrhythmia are factors that increase pulmonary vascular resistance (PVR) and pulmonary pressures, deteriorate right ventricular function, and lead to hemodynamic collapse and death.[4],[7] For all these reasons, the induction of anesthesia and the initiation of mechanical ventilation are challenging and critical moments in perioperative management. The anesthetic-agent-induced systemic vasodilatation and mechanical ventilation can lead to a significant drop in mean arterial pressure, reduce coronary perfusion pressure, and affect right ventricular contractility.[6] The most dangerous perioperative complication is hypotension due to right ventricular failure from the exacerbation of PH.[5] The anesthesia administration may expose patients to apnea and hypoventilation, hypoxemia, fluctuations of body temperature, hypotension, and sympathetic stimulations.[8] Oxygen is systematically used before anesthesia initiation to increase oxygen reserves and safe apnea.[9] Nitric oxide (NO), an endogenous mediator produced from the vascular endothelium, is a powerful vasodilator and is used in intensive care through inhalation (iNO) as a selective pulmonary vasodilator.[10],[11],[12],[13] The iNO decreases the PVR and the shunt effect, and it improves oxygenation by the optimization of the ventilation-perfusion ratio.[12],[13],[14] The short lifetime of iNO (approximately 6 s) allows a fast metabolism without inducing any undesirable effects, such as systemic hypotension.[15]

We hypothesize that iNO added to oxygen should decrease pulmonary artery pressure and avoid PH crisis during anesthesia induction.

   Materials and Methods Top

This prospective, interventional, single-center trial was approved by the regional research ethics committee (CPP Sud-Est VI, date December 04, 2015, Axelle Van Lander) and registered with EudraCT (N°: 2014-003338-15) and on (N°: NCT02345616).

The inclusion criteria were that patients must be scheduled for heart surgery with sternotomy and cardiopulmonary bypass (CPB), be aged >18 years with PH class 2 according to the Dana Point classification, and should have a systolic pulmonary arterial pressure (PASP) of >40 mmHg diagnosed by preoperative right cardiac catheterization or by transthoracic echocardiography. The exclusion criteria were patients who have had a heart transplant, have a PH of type 1, 4, or 5 according to the Dana Point classification, have methemoglobin reductase deficit, or have an incapacity to understand the protocol and sign their consent.

Patients received a detailed explanation of the study during preoperative consultation and have signed their consent according to the modalities described by the Code of Public Health System.

On the evening before surgery and 1 h before anesthesia, the patients received of hydroxyzine. Upon arrival at the operating theatre, they were equipped with one large peripheral intravenous line, a radial arterial line, five-lead electrocardiography, a bispectral index monitor, a pulse-oximetry, and a muscular relaxation monitoring. A central venous catheter and a pulmonary artery catheter (PAC) were inserted under local anesthesia. The right internal jugular vein was localized with the help of an ultrasound machine equipped with a high-frequency linear probe. After administration of local anesthesia at the right jugular region, a central venous catheter and a 7.5F volumetric continuous cardiac output pulmonary artery catheter (Edwards Lifesciences Corporation, One Edwards Way, Irvine, CA 92614) were inserted under the out-of-plane ultrasound-guided technique. The PAC was connected to a Vigilance II monitor (Edwards Lifesciences Corporation, One Edwards Way, Irvine, CA 92614). Arterial blood gas was realized in room air. The mixed venous oxygen saturation (SvO2) measurement was performed and in-vivo calibration was performed on the Vigilance II monitor. Before proceeding to measurements, a 3-min pause was made to obtain stabilized hemodynamic measurement data as recommended by the Vigilance II monitor constructor.

We measured the following hemodynamic parameters: heart rate (HR), systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), PASP, pulmonary arterial mean pressure (PAMP), pulmonary arterial diastolic pressure (PADP), SvO2, continuous cardiac output (CCO), cardiac index (CI), right ventricular end-diastolic volume (RVEDV), right ventricular ejection fraction (RVEF), and stroke volume (SV). Based on these measurements, we calculated the following hemodynamic parameters: systemic vascular resistance (SVR), oxygen delivery (DO2), oxygen consumption (VO2), and the PAMP/MAP ratio. We measured the following respiratory parameters: peripheral oxygen saturation (SpO2), inspired oxygen fraction (FiO2), expired oxygen fraction (FeO2), minute volume (MV), pH, arterial oxygen saturation (SatO2), the partial pressure of arterial oxygen concentration (PaO2), the partial pressure of carbon dioxide arterial concentration (PaCO2), and methemoglobin concentration (MetHb).

All the hemodynamic and respiratory measurements were performed initially at room air which corresponds to T0. Afterward, we started oxygenation with a face mask at 10 L/min (20 ppm) of 100% oxygen via a closed breathing circuit while monitoring the patient's spirometry and other respiratory parameters [Figure 1]. All the hemodynamic and respiratory parameters were obtained every minute for 5 min (T1, T2, T3, T4, and T5). A second arterial blood gas analysis was performed at the end of T5. The iNO at 1.2 L/min was added to oxygen from 6 min to 10 min (T6, T7, T8, T9, T10). All the hemodynamic and respiratory parameters were noted. A third arterial blood gas analysis was performed at the end of the T10 [Figure 2]. After T10 the anesthesia induction was done in the standard way. The iNO weaned progressively after anesthesia induction and orotracheal intubation.
Figure 1: Figure diagram of the circuit used to show the iNO delivery

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Figure 2: Flow chart

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Statistical analysis

Statistical analysis was performed using Stata software, version 13 (StataCorp, College Station, TX, US). The tests were two-sided with a type I error set at α = 0.05. Quantitative data were presented as the mean ± standard deviation (SD) or the median (interquartile range) according to statistical distribution (assumption of normality assessed by using the Shapiro-Wilk test). To consider between-patient and within-patient interaction (due to several measures for a single subject), random-effects for correlated measures (random intercept and slope with independent covariance structure) were performed, rather than the usual statistical tests that would not be appropriate due to the hypothesis of independence data not being verified. The normality of residuals from these models has been studied using the Shapiro-Wilk test. When appropriate, a logarithmic transformation was proposed to achieve the normality of dependent data. A Sidak's correction of the type I error was applied to consider multiple comparisons.

   Results Top

Ten patients were included in the study (3 males and 7 females). The patient characteristics are presented in [Table 1]. The respiratory and oxygenation parameters measured in room air, after 5 min of oxygen and iNO breathing are shown in [Table 2]. A 100% hemoglobin saturation in all patients breathing oxygen with a face mask was achieved after 3 min. The addition of iNO to oxygen did not further increase oxygenation as expected. The complete hemodynamic parameters are shown in [Table 3]. The oxygen alone did not decrease PAMP. The addition of iNO decreased PAMP and PADP compared to room air (P = 0.01) and oxygen (P < 0.001), as presented in [Table 3] and [Figure 3]. The PAMP and PADP decrease, against all expectations, was associated with a slight increase of RVEDV, a slight decrease of RVEF, and a slight decrease of the CI in the second part when iNO was added to oxygen. The increased arterial blood oxygenation increased SvO2 and decreased linearly the VO2 (P < 0,001).
Figure 3: Mean pulmonary arterial pressure

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Table 1: Patients characteristics

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Table 2: Respiratory parameters

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Table 3: Hemodynamic parameters

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   Discussion Top

Inhaled nitric oxide therapy as a selective pulmonary vasodilator in cardiac surgery has been one of the most significant pharmacological advances in managing pulmonary hemodynamics and life-threatening right ventricular dysfunction and failure.[16],[17] To our knowledge, this is the first study that evaluates every step-in real-time the effect of oxygen and iNO in respiratory and hemodynamic parameters before another intervention like anesthesia or surgery, measured with a precise accuracy with the help of a volumetric pulmonary catheter.

The primary findings of this study were as follows: 1) oxygen did not decrease pulmonary pressure; (2) the addition of iNO to oxygen decreases pulmonary pressure; 3) the addition of iNO to oxygen did not further improve oxygenation through improved ventilation-perfusion ratio; 4) the increase of arterial blood oxygen content, decreases peripheral oxygen consumption.

Pure oxygen administration increases PaO2 and, progressively, the FeO2. The addition of iNO to O2 should logically further increase the PaO2 by improving the ventilation-perfusion ratio as described before.[13] This did not happen to our patients, the PaO2 does not increase further with iNO. This can be explained since our patients are not hypoxemic, their basic PaO2 is 77 mmHg in room air. This phenomenon is emphasized in the review of Rao et al.[18] Probably the patients do not have important lung portions with hypoxic vasoconstriction and an important intrapulmonary right to left shunting.

Breathing pure oxygen should decrease pulmonary arterial pressure and right ventricular afterload since it is well-known that oxygen has a vasodilatory effect on the pulmonary circulation. This was not reported in our study.

The addition of iNO to oxygen as a selective pulmonary vasodilator decreases pulmonary arterial pressure, as shown in other studies.[16] This pulmonary arterial pressure decrease is not associated with improved right ventricular performance with the decrease of right ventricular end-diastolic volume and the increase of right ventricular ejection fraction as expected. The oxygen and iNO administration did not increase the cardiac index and right ventricular ejection fraction like it did in other studies.[17] This can be explained that iNO has limited action only in the vascular endothelium and does not change the underlying mitral or left ventricular pathology. Only cardiac surgery constitutes the therapeutic alternative to treat the causal underlying condition.[19]

Ventilation with pure oxygen, or hyperoxic ventilation (HV), is thought to decrease whole-body oxygen consumption.[20] We found the same phenomenon: the VO2 decreases when the patient breathes pure oxygen and decreases further when iNO is added to O2.

Another interesting finding is that ventilation with oxygen and iNO increases indexed systemic vascular resistances (ISVR) and like in the other studies proves that iNO rapidly scavenged by oxyhemoglobin and has no systemic vasodilating effects.[14] The ISVR probably happens because of hyperoxic arteriolar constriction and reduced functional capillary density, which reduces nutritive organ blood flow and increases peripheral oxygen shunting.[20] The increase in arterial oxygen content by breathing 100% oxygen with constant oxygen peripheral consumption, explains the DO2 increase and VO2 decrease in our study. The iNO inhalation has no side effects, and the MetHb level is low. Breathing 100% O2 significantly decreases oxygen consumption and optimizes oxygen delivery—oxygen consumption balance.[20] The iNO treatment could have another positive protective effect on ischemia-reperfusion damage as demonstrated in more recent discoveries.[21],[22]

The limits of this study are the small number of patients included and lack of control group. We are convinced that the inclusion of more patients would not modify the current findings. All the patients included belong to group 2 Dana Point classification of PH and our results could be specific to this group of patients. We considered that a control group is not necessary since every patient represents an intraindividual control through the three steps of the study (during room air, oxygen, and iNO administration). Another limit is the absence of some hemodynamic parameters due to the unexplained non-measurements from the Vigilance II monitor. It should be emphasized that the authors tried to obtain the most accurate values. The SvO2 was measured with reflection spectrophotometry and the Vigilance II monitor uses thermal energy to calculate cardiac output using thermodilution principles. It was impossible in our study to measure the pulmonary arterial occlusive pressure every minute and PVR cannot be measured without this parameter. The VO2, DO2, and ISVR were calculated by the authors in an excel sheet using classical hemodynamic formulas for these parameters. All these parameters cannot be displayed in real-time by the monitor. The pulmonary pressure reduction in our study cannot be related to the reduced amount of blood entering the pulmonary circulation since the central venous pressure (CVP) is constant.

In conclusion, the results of this study confirm that administration of iNO with a face mask is a safe and effective method to reduce pulmonary arterial pressure before the induction of anesthesia in patients with PH. Oxygen and hyperoxia influence systemic vascular resistance and peripheral oxygen consumption.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Vedat Eljezi
Praticien Hospitalier, CHU Clermont-Ferrand, Pôle Médecine Périoperatoire, Chirurgie Cardio-Vasculaire, F-63003 Clermont-Ferrand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aca.ACA_82_20

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