GENOSYL- nitric oxide gas

GENOSYL by

Drug Labeling and Warnings

GENOSYL by is a Prescription medication manufactured, distributed, or labeled by VERO BIOTECH, INC.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use GENOSYL® safely and effectively. See full prescribing information for GENOSYL. GENOSYL (nitric oxide), for inhalation use
Initial U.S. Approval: 1999

INDICATIONS AND USAGE

GENOSYL is a vasodilator indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents (1).

DOSAGE AND ADMINISTRATION

The recommended dose is 20 ppm, maintained for up to 14 days or until the underlying oxygen desaturation has resolved (2.1).

Doses greater than 20 ppm are not recommended (2.1, 5.2).

Administration: Avoid abrupt discontinuation (2.2, 5.1).

DOSAGE FORMS AND STRENGTHS

GENOSYL (nitric oxide) is a gas, available at concentrations up to 800 ppm. (3)

CONTRAINDICATIONS

Neonates dependent on right-to-left shunting of blood (4).

WARNINGS AND PRECAUTIONS

Rebound Pulmonary Hypertension: Abrupt discontinuation of GENOSYL may lead to worsening oxygenation and increasing pulmonary artery pressure (5.1).

Methemoglobinemia: Methemoglobin increases with the dose of nitric oxide; following discontinuation or reduction of nitric oxide, methemoglobin levels return to baseline over a period of hours (5.2).

Elevated NO2 Levels: Monitor NO2 levels (5.3).

Heart Failure: In patients with pre-existing left ventricular dysfunction, GENOSYL may increase pulmonary capillary wedge pressure leading to pulmonary edema (5.4).

ADVERSE REACTIONS

The most common adverse reaction is hypotension (6).

To report SUSPECTED ADVERSE REACTIONS, contact Vero Biotech at 1-877-337-4118 and http://www.vero-biotech.com/ or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Nitric oxide donor compounds may increase the risk of developing methemoglobinemia (7).

Revised: 12/2022
Table of Contents

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

2.2 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation

5.2 Hypoxemia from Methemoglobinemia

5.3 Airway Injury from Nitrogen Dioxide

5.4 Worsening Heart Failure

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Nitric Oxide Donor Agents

8 USE IN SPECIFIC POPULATIONS

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Treatment of Hypoxic Respiratory Failure (HRF)

14.2 Ineffective in Adult Respiratory Distress Syndrome (ARDS)

14.3 Ineffective in Prevention of Bronchopulmonary Dysplasia (BPD)

16 HOW SUPPLIED/STORAGE AND HANDLING

* Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

GENOSYL® is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

Term and near-term neonates with hypoxic respiratory failure

The recommended dose of GENOSYL is 20 ppm. Maintain treatment up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from GENOSYL therapy.

Doses greater than 20 ppm are not recommended [see Warnings and Precautions (5.2)].

2.2 Administration

Nitric Oxide Delivery System

GENOSYL must be administered using a calibrated GENOSYL Delivery System. Only validated ventilator systems should be used in conjunction with GENOSYL [see Description (11)].

Consult the GENOSYL Delivery System Operator's Manual or call 1-877-337-4118 or visit www.vero-biotech.com for needed information on training and technical support for users of GENOSYL with the GENOSYL Delivery System .

Keep available a backup power supply to address power failures. The GENOSYL Delivery System consists of a primary system and a fully functional second system that can be used as backup in the event of primary system failure.

Monitoring

Measure methemoglobin within 4-8 hours after initiation of treatment with GENOSYL and periodically throughout treatment [see Warnings and Precautions (5.2)].

Monitor for PaO2 and inspired NO2 during GENOSYL administration [see Warnings and Precautions (5.3)].

Weaning and Discontinuation

Avoid abrupt discontinuation of GENOSYL [see Warnings and Precautions (5.1)]. To wean GENOSYL, down titrate in several steps, pausing several hours at each step to monitor for hypoxemia.

3 DOSAGE FORMS AND STRENGTHS

GENOSYL (nitric oxide) is a gas available at concentrations up to 800 ppm [see Description (11)].

4 CONTRAINDICATIONS

GENOSYL is contraindicated in neonates dependent on right-to-left shunting of blood.

5 WARNINGS AND PRECAUTIONS

5.1 Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation

Wean from GENOSYL [see Dosage and Administration (2.2)]. Abrupt discontinuation of GENOSYL may lead to worsening oxygenation and increasing pulmonary artery pressure, i.e., Rebound Pulmonary Hypertension Syndrome. Signs and symptoms of Rebound Pulmonary Hypertension Syndrome include hypoxemia, systemic hypotension, bradycardia, and decreased cardiac output. If Rebound Pulmonary Hypertension occurs, reinstate GENOSYL therapy immediately.

5.2 Hypoxemia from Methemoglobinemia

Nitric oxide combines with hemoglobin to form methemoglobin, which does not transport oxygen. Methemoglobin levels increase with the dose of GENOSYL; it can take 8 hours or more before steady-state methemoglobin levels are attained. Monitor methemoglobin and adjust the dose of GENOSYL to optimize oxygenation.

If methemoglobin levels do not resolve with decrease in dose or discontinuation of GENOSYL, additional therapy may be warranted to treat methemoglobinemia [see Overdosage (10)].

5.3 Airway Injury from Nitrogen Dioxide

Nitrogen dioxide (NO2) forms in gas mixtures containing NO and O2. Nitrogen dioxide may cause airway inflammation and damage to lung tissues.

If there is an unexpected change in NO2 concentration, or if the NO2 concentration reaches 0.5 ppm when measured in the breathing circuit, then the delivery system should be assessed in accordance with the GENOSYL Delivery System Operator's Manual troubleshooting section, and the NO2 analyzer should be recalibrated. The dose of GENOSYL and/or FiO2 should be adjusted as appropriate.

5.4 Worsening Heart Failure

Patients with left ventricular dysfunction treated with GENOSYL may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest. Discontinue GENOSYL while providing symptomatic care.

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in the label;

Hypoxemia [see Warnings and Precautions (5.2)]

Worsening Heart Failure [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Controlled studies have included 325 patients on nitric oxide doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on nitric oxide gas for inhalation, a result adequate to exclude nitric oxide mortality being more than 40% worse than placebo.

In both the NINOS and CINRGI studies, the duration of hospitalization was similar in nitric oxide gas for inhalation and placebo-treated groups.

From all controlled studies, at least 6 months of follow-up is available for 278 patients who received nitric oxide gas and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for re-hospitalization, special medical services, pulmonary disease, and neurological sequelae.

In the NINOS study, treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage.

In CINRGI, the only adverse reaction (>2% higher incidence on nitric oxide gas for inhalation than on placebo) was hypotension (14% vs. 11%).

6.2 Post-Marketing Experience

Post marketing reports of accidental exposure to nitric oxide for inhalation in hospital staff have been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.

7 DRUG INTERACTIONS

7.1 Nitric Oxide Donor Agents

Nitric oxide donor agents such as prilocaine, sodium nitroprusside and nitroglycerine may increase the risk of developing methemoglobinemia.

8 USE IN SPECIFIC POPULATIONS

8.4 Pediatric Use

The safety and efficacy of nitric oxide for inhalation has been demonstrated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension [see Clinical Studies (14.1)]. Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy [see Clinical Studies (14.3)]. No information about its effectiveness in other age populations is available.

8.5 Geriatric Use

Nitric oxide is not indicated for use in the adult population.

10 OVERDOSAGE

Overdosage with nitric oxide gas is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO2. Elevated NO2 may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, nitric oxide gas.

Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.

11 DESCRIPTION

GENOSYL (nitric oxide) is administered by inhalation. Nitric oxide is a pulmonary vasodilator. Nitric oxide is generated from liquid dinitrogen tetroxide (N2O4) by the cassette in the GENOSYL Delivery System. Upon initiation of GENOSYL Delivery System, the liquid N2O4 is heated and the equilibrium shifts to nitrogen dioxide (NO2) gas. The NO2 is then converted into nitric oxide (NO) using the antioxidant cartridges, and nitric oxide is delivered to the patient by means of a ventilator or a nasal cannula. The amount of nitric oxide administered to the patient is set by controlling the temperature of the N2O4 liquid module, which controls the pressure inside the liquid module, which in turn controls the mass of NO2 that is sent to the primary cartridges, and hence the mass of nitric oxide. The mass flow of nitric oxide, together with the air from the pump, control the nitric oxide concentration. A nitric oxide sensor monitors the nitric oxide in the patient line. GENOSYL Delivery System is designed to deliver a controlled level of nitric oxide blended with breathing air or oxygen-enriched breathing air.

The GENOSYL Delivery System controls the flow of nitric oxide mixed with air delivered to the patient.

The structural formula of nitric oxide (NO) is shown below:

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature.

GENOSYL appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

12.2 Pharmacodynamics

Effects on Pulmonary Vascular Tone in PPHN

Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, nitric oxide gas for inhalation improves oxygenation (as indicated by significant increases in PaO2).

12.3 Pharmacokinetics

The pharmacokinetics of nitric oxide has been studied in adults.

Absorption and Distribution

Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate.

Metabolism

Methemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration-time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm nitric oxide are shown in Figure 1.

Methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. The mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm nitric oxide gas groups, but reached approximately 5% in the 80 ppm nitric oxide gas group. Methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours.

Elimination

Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have not been investigated.

Nitric oxide gas has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. There are no animal or human studies to evaluate nitric oxide for effects on fertility.

14 CLINICAL STUDIES

14.1 Treatment of Hypoxic Respiratory Failure (HRF)

The efficacy of nitric oxide gas was investigated in term and near-term newborns with hypoxic respiratory failure (HRF) resulting from a variety of etiologies. Inhalation of nitric oxide gas reduces the oxygenation index (OI= mean airway pressure in cm H2O × fraction of inspired oxygen concentration [FiO2]× 100 divided by systemic arterial concentration in mm Hg [PaO2]) and increases PaO2 [see Clinical Pharmacology (12.1)].

NINOS Study

The Neonatal Inhaled Nitric Oxide Study (NINOS) was a double-blind, randomized, placebo-controlled, multicenter trial in 235 neonates with hypoxic respiratory failure. The objective of the study was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy. Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%). Infants ≤14 days of age (mean, 1.7 days) with a mean PaO2 of 46 mmHg and a mean oxygenation index (OI) of 43 cm H2O / mmHg were initially randomized to receive 100% O2 with (n=114) or without (n=121) 20 ppm nitric oxide for up to 14 days. Response to study drug was defined as a change from baseline in PaO2 30 minutes after starting treatment (full response = >20 mmHg, partial = 10-20 mmHg, no response = <10 mmHg). Neonates with a less than full response were evaluated for a response to 80 ppm nitric oxide or control gas. The primary results of this study are presented in Table 1.

Table 1: Summary of Clinical Results from Hypoxic Respiratory Failure Study
	Control (n=121)	Nitric Oxide gas (n=114)	P value
* Extracorporeal membrane oxygenation † Death or need for ECMO was the parimary end point of this study
Death or ECMO*†	77 (64%)	52 (46%)	0.006
Death	20 (17%)	16 (14%)	0.60
ECMO	66 (55%)	44 (39%)	0.014

Although the incidence of death by 120 days of age was similar in both groups (NO, 14%; control 17%), significantly fewer infants in the nitric oxide group required ECMO compared with controls (39% vs. 55%, p = 0.014). The combined incidence of death and/or initiation of ECMO showed a significant advantage for the nitric oxide treated group (46% vs. 64%, p = 0.006). The nitric oxide group also had significantly greater increases in PaO2 and greater decreases in the OI and the alveolar-arterial oxygen gradient than the control group (p<0.001 for all parameters). Significantly more patients had at least a partial response to the initial administration of study drug in the nitric oxide group (66%) than the control group (26%, p<0.001). Of the 125 infants who did not respond to 20 ppm nitric oxide control, similar percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80 ppm nitric oxide gas for inhalation or control drug, suggesting a lack of additional benefit for the higher dose of nitric oxide. No infant had study drug discontinued for toxicity. Inhaled nitric oxide gas had no detectable effect on mortality. The adverse events collected in the NINOS trial occurred at similar incidence rates in both treatment groups [see Adverse Reactions (6.1)]. Follow-up exams were performed at 18-24 months for the infants enrolled in this trial. In the infants with available follow-up, the two treatment groups were similar with respect to their mental, motor, audiologic, or neurologic evaluations.

CINRGI Study

This study was a double-blind, randomized, placebo-controlled, multi-center trial of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory failure. The primary objective of the study was to determine whether nitric oxide gas would reduce the receipt of ECMO in these patients. Hypoxic respiratory failure was caused by MAS (35%), idiopathic PPHN (30%), pneumonia/sepsis (24%), or RDS (8%). Patients with a mean PaO2 of 54 mmHg and a mean OI of 44 cm H2O / mmHg were randomly assigned to receive either 20 ppm nitric oxide gas (n=97) or nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a PaO2 >60 mmHg and a pH < 7.55 were weaned to 5 ppm nitric oxide gas or placebo. The primary results from the CINRGI study are presented in Table 2.

Table 2: Summary of Clinical Results from Persistent Pulmonary Hypertension of the Newborn Study
	Placebo	Nitric oxide gas	P value
* Extracorporeal membrane oxygenation † ECMO was the primary end point of this study
ECMO*†	51/89 (57%)	30/97 (31%)	<0.001
Death	5/89 (6%)	3/97 (3%)	0.48

Significantly fewer neonates in the nitric oxide gas group required ECMO compared to the control group (31% vs. 57%, p<0.001). While the number of deaths were similar in both groups (Nitric oxide gas, 3%; placebo, 6%), the combined incidence of death and/or receipt of ECMO was decreased in the nitric oxide gas group (33% vs. 58%, p<0.001).

In addition, the nitric oxide gas group had significantly improved oxygenation as measured by PaO2, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with nitric oxide gas, 2 (2%) were withdrawn from study drug due to methemoglobin levels >4%. The frequency and number of adverse events reported were similar in the two study groups [see Adverse Reactions (6.1)].

In clinical trials, reduction in the need for ECMO has not been demonstrated with the use of inhaled nitric oxide in neonates with congenital diaphragmatic hernia (CDH).

14.2 Ineffective in Adult Respiratory Distress Syndrome (ARDS)

In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ARDS) associated with pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO2/FiO2 <250 mmHg despite optimal oxygenation and ventilation, received placebo (n=193) or nitric oxide gas (n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation. Despite acute improvements in oxygenation, there was no effect of nitric oxide gas on the primary endpoint of days alive and off ventilator support. These results were consistent with outcome data from a smaller dose ranging study of nitric oxide (1.25 to 80 ppm). GENOSYL (nitric oxide) for inhalation is not indicated for use in ARDS.

14.3 Ineffective in Prevention of Bronchopulmonary Dysplasia (BPD)

The safety and efficacy of nitric oxide gas for the prevention of chronic lung disease [bronchopulmonary dysplasia (BPD)] in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in four large previously conducted multicenter, double-blind, placebo-controlled clinical trials in a total of 2,600 preterm infants. Of these, 1,290 received placebo, and 1,310 received inhaled nitric oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration. The primary endpoint for these studies was alive and without BPD at 36 weeks postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a surrogate endpoint for the presence of BPD. Overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established. There were no meaningful differences between treatment groups with regard to overall deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity.

The use of GENOSYL (nitric oxide) for prevention of BPD in preterm neonates ≤34 weeks gestational age is not recommended.

16 HOW SUPPLIED/STORAGE AND HANDLING

GENOSYL Delivery System cassettes produce at least 216 liters of 800 ppm nitric oxide gas (at standard temperature and pressure, STP) (NDC: 72385-002-01).

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

The GENOSYL Delivery System must be used with antioxidant cartridges not older than 12 months from the manufacturing date.

Occupational Exposure

The exposure limit set by the Occupational Safety and Health Administration (OSHA) for nitric oxide is 25 ppm, and for NO2 the limit is 5ppm.

SPL UNCLASSIFIED SECTION

Rx Only

VERO Biotech and GENOSYL are registered trademarks of VERO Biotech.

Manufactured by:
VERO BIOTECH
387 Technology Circle NW
Suite 125
Atlanta, GA 30313, USA
[602604]

INSTRUCTIONS FOR USE

Vero Biotech Inc.
387 Technology Circle NW, Suite 125
Atlanta, GA 30313 USA

WARNINGS, CAUTIONS, AND NOTES

Please read all warnings and cautions in this Operator's Manual prior to using the GENOSYL DS.

MR Conditional Safety Information

The GENOSYL DS may be safely used in the MR environment under the following conditions. Failure to follow these conditions may result in injury.

Maximum static magnetic field of 100 Gauss (0.01mT)
Device remains outside the scanner bore
Preparation protocols described in the Warnings section titled "Use in the MR Environment" must be followed before MR procedure

Image Artifacts:

When the GENOSYL DS is battery powered, no image artifacts are expected. When powered using a wall outlet, minor noise is expected.

Throughout this Operator's Manual, warning, cautions, and notes will be displayed in the following manner.

WARNING
The warning box will alert the user to possible injury, death, or serious adverse reactions associated with the use or misuse of the device.

CAUTION
The caution box will alert the user about proper use of the equipment and any conditions that could result in equipment damage or failure. The user should read and adhere to all warnings and cautions.

NOTE
The note box provides information, clarification, or supplemental information to assist and educate the user on the use of the equipment.

A complete list of Warnings and Cautions for the GENOSYL DS are shown below. Where appropriate, some of these will also be shown throughout this manual.

WARNINGS
Please consult the package insert for a complete list of contraindications.
Alarms ALWAYS acknowledge and follow information provided from alarms. An alarm indicates an abnormal condition, and ignoring alarms can result in possible injury, death, or serious adverse reactions. ALWAYS use clinical judgement when setting upper or lower alarm limits. Failure to do so could result in possible injury or death.
Consoles ALWAYS have a second Console present and properly connected when a Dosing Console is connected to the patient. If the Dosing Console malfunctions, switch to the Back-up Console. If the Back-up Console is not available or properly connected, this may result in patient injury or death. DO NOT clean the GENOSYL DS with the power connected and the System turned ON, as this may lead to injury (e.g., shock). Unplug AC/DC power supply external to the System prior to cleaning. NEVER modify the equipment. Modifications of the equipment may result in malfunction, which may result in a fire, shock, injury, or death. NEVER turn the rear power switch OFF until the System has gone through a controlled shutdown or instructed by VERO Technical Support. Turning the rear power switch OFF prematurely (e.g., while it is still in use) will immediately shut down the device. This may result in interruption in NO delivery to the patient, which may cause injury or death.
Cassette DO NOT use the Cassette if the Cassette State Window is not blue. A Cassette State Window that is any color other than blue may affect the Cassette's ability to provide the correct NO dosage to the patient, which may cause injury or death. DO NOT use a Cassette that is beyond its expiration date. Using an expired Cassette may affect the Cassette's ability to provide the correct NO dosage to the patient, which may cause injury or death. MAKE SURE the System stabilizes to the prescribed concentration (ppm) of NO prior to leaving the Console unattended. Failure to do so could result in under delivery of the target NO, leading to injury or harm. ALWAYS replace a Cassette once depleted. A depleted Cassette will interrupt patient dosing and can lead to under dosing and/or injury to the patient. ALWAYS follow Cassette inspection instructions prior to Cassette insertion. Not inspecting the Cassette prior to insertion may lead to using a faulty Cassette, resulting in injury.
Use in the MR Environment The GENOSYL DS is classified as MR Conditional with MR scanners of 1.5 or 3.0 Tesla strength ONLY in areas where the field strength is less than 100 gauss. ALWAYS operate at a fringe field of less than 100 gauss. This device contains ferromagnetic components and may experience strong attraction close to the magnet. DO NOT exceed 100 gauss; System operation may be impacted. Confirm Cart caster lock function. Optionally connect tether. NEVER use the GENOSYL DS in the MR scanner room without gauss alarms installed. ALWAYS verify at least one gauss alarm is functioning properly prior to use in the MR environment. DO NOT use the GENOSYL DS in the MR environment if neither gauss alarm is functional. ALWAYS move System away from the MR scanner if the gauss alarm sounds. The gauss alarm will sound if the System is too close to the MR scanner. Move System away from the MR scanner until the gauss alarm stops sounding. ALWAYS verify that the GENOSYL DS Cart casters are locked after positioning the System in the MR scanner room. ALWAYS verify that the GENOSYL DS is securely attached to the Cart. ALWAYS arrange power cord, MR patient gas sample line, and NO delivery line to avoid entanglement, strangulation and/or a trip hazard. DO NOT use the GENOSYL DS in the MR environment if the Cart moves when the brake caster locks are engaged. NEVER perform NO or NO2 calibration within the MR scanner room. Calibration equipment is a potential projectile hazard.
Connections ALWAYS follow pre-use setup instructions for the routing and connections of tubing to avoid patient strangulation. MAKE SURE the System has all tubing connected as described in the instructions. Not connecting all tubing may result in inaccurate dosage and harm the patient. NEVER touch the electrical connectors of the System or its accessories, and the patient simultaneously. If the user touches another device with a ground-fault failure and simultaneously touches the GENOSYL DS, this can result in injury (e.g., shock) should a grounding failure be present.
Battery ONLY properly trained personnel should replace the battery. Incorrectly replacing the battery may result in a hazard such as excessive temperatures, fire, or explosion. MAKE SURE the GENOSYL DS is connected to AC wall power to charge the battery a minimum of once every 3 months to maintain a minimum battery charge. Failure to recharge the Console battery for extended timeframes may result in full discharge of the battery. If a Battery Error message occurs during startup of the System, contact Technical Support at 877-337-4118 for assistance.
User ONLY intended users who are experienced in the use of this System should use this device. US federal law restricts device use to licensed medical professionals. If device is used by unintended users, device can be misused and lead to injury or death.
Alternative Means of Ventilation ALWAYS ensure that the manual flow displayed on the Console matches the flow set into the resuscitation bag. Incorrect flow settings may result in an incorrect estimation of NO delivery. If the flow into the manual equipment is too low, there is risk of overdosing the patient with NO. ALWAYS squeeze the bag several times, after starting fresh gas flow, to empty residual gas in the bag prior to using the System to ventilate a patient. Failure to do so could result in higher NO2 levels being delivered to the patient. ALWAYS use the smallest bag adequate to deliver the desired tidal volume. Failure to do so could result in higher NO2 levels being delivered to the patient.
Patient Monitoring ALWAYS constantly monitor the patient. System malfunctions can occur if device and patient are not monitored and can result in injury or death. Careful monitoring is required by care personnel whenever the System is used on a patient. The use of an alarm and a monitoring system does not give an absolute assurance of warning for every malfunction that may occur. Certain alarms may require immediate response.
Use with Breathing Devices DO NOT use the GENOSYL DS with circle anesthesia ventilator systems. The GENOSYL DS has not been characterized or qualified for use with anesthesia breathing systems with recirculation of gases. ONLY use a manual resuscitation bag with the GENOSYL DS for a short time (e.g., less than one hour) when on battery only. Otherwise, the System may shut off and may result in injury or death. ALWAYS ensure the trigger sensitivity of the ventilator is checked after connecting the GENOSYL DS to the breathing circuit. The GENOSYL DS injects and samples gas from the patient respiratory circuit which may affect the triggering sensitivity of the ventilator. ALWAYS ensure the patient disconnect and high-pressure alarms are used with the ventilator. Otherwise, the System is not working properly. ONLY use the GENOSYL DS with Bio-Med Crossvent 2+/2i+ with Constant Flow ON. Not doing so may lead to elevated NO2 levels or dose variability.
Set-up ONLY VERO Biotech authorized equipment technicians are to perform the initial System set-up prior to initial use. Failure to use an authorized equipment technician can result in a patient or user injury. ONLY store the GENOSYL DS as outlined in the storage instructions. Not storing the device in alignment with its storage instructions can cause the device to be unsafe and lead to injury or death. AVOID using the GENOSYL DS adjacent to or stacked with other equipment, as it may result in improper operation. If such use is necessary, this equipment and the other equipment should be observed to verify that they are operating normally. DO NOT use accessories or cables other than those specified or provided by the manufacturer of this equipment, as this may result in increased electromagnetic emissions or decreased electromagnetic immunity of this equipment and result in improper operation. DO NOT place portable RF communications equipment (including peripherals such as antenna cables and external antennas) closer than 30cm (12 inches) to any part of the GENOSYL DS, including cables specified. Otherwise, degradation of the performance of this equipment could occur, resulting in injury. Only connect to a power outlet with protective earth. Failure to connect to an outlet with protective earth may result in an electrical shock.
Troubleshooting ALWAYS ensure patient safety before troubleshooting (such as an activated alarm) or replacing a problematic item. Not monitoring the patient prior to attending to an alarm can result in injury or death.
Calibration ONLY use the calibration gas pressure regulators supplied by the manufacturer. Pressure regulators not supplied by the manufacturer may damage the sensors and may lead to patient injury. ALWAYS verify the correct NIST traceable calibration gas is being used and confirm the expiration date of the calibration gas prior to performing calibration. The use of incorrect or expired gas may result in inaccurate sensor readings and can lead to patient injury.
Cleaning and Maintenance NEVER submerge the GENOSYL DS, Cassettes, or non-disposable Adaptive Sensor Cable. Submerging in liquids will damage the System and could cause electrical shorts which may result in injury or death.
Water Trap ALWAYS empty Water Trap when prompted by the System, and when the trap is more than half full. Allowing the Water Trap to completely fill will occlude the Sample Line which will interrupt patient gas NO, NO2, and O2 concentration monitoring. Failure to monitor the patient gas NO, NO2, and O2 concentrations may result in patient injury. ALWAYS conduct Water Trap/ Sample Line Leak Test every time you empty and replace the Water Trap, as failure to do so may lead to an incorrect NO reading, which can result in injury or death. ALWAYS use a Water Trap supplied by the manufacturer. Using an incorrect Water Trap could result in non-functioning or inaccurate sensor readings.
Use Outside of Product Labeling ALWAYS use the GENOSYL DS in accordance with the indications, usage, contraindications, warnings, and precautions described in the GENOSYL prescribing information and labeling. Refer to latest approved prescribing information and labeling prior to use. The approved patient population for the GENOSYL DS as specified in the drug labeling for GENOSYL (nitric oxide) for inhalation, is limited to neonates. The GENOSYL DS is not intended to be used in other patient populations. ONLY use the GENOSYL DS, its parts, and accessories as instructed. Using non-specified components may result in product malfunction, injury, or death ONLY trained personnel should operate the GENOSYL DS. Failure to do so can result in injury or death. ONLY mechanical ventilators validated with the GENOSYL DS should be used. Not using a validated ventilator system can result in injury or harm.

CAUTIONS
Supplied Instructions ALWAYS refer to the instructions supplied with all equipment to be used in conjunction with the GENOSYL DS for their intended uses, contraindications, and potential complications. Misuse of the device or its components may damage the device.
Cassette DO NOT remove Cassette from packaging until ready to use. External packaging is designed to protect the Cassette from damage and/or contamination. User should always have a secondary Cassette inserted in the Dosing Console and preheated in order for auto transition to occur. User should replace depleted Cassette as soon as possible after ejection.
Consoles ALWAYS operate the Console on a level surface to avoid potential interruption to Nitric Oxide (NO) delivery. ONLY use recommended cleaning agents or a damp cloth to clean the Console and limit use of liquids around Console. Excess water can permanently damage the device. ONLY use the GENOSYL DS with the power cord supplied by the manufacturer. Use of a generic power cord may cause output voltage instability leading to a touch screen failure. ALWAYS ensure the power cord is firmly seated into the power supply and the wall outlet. A loose connection can result in damage to the device or faulty operation. Prolonged use in dry environments without humidification will damage the gas sensors. Supplemental humidification providing greater than 20% relative humidity (RH) in the patient circuit is recommended.
Calibration ALWAYS perform a full-scale calibration of the GENOSYL DS when prompted by the System prior to use. ALWAYS confirm the correct flow direction of the installed one-way check valve in the sampling tee to avoid over pressurization of the sample System and damage to the device.
Cleaning and Maintenance ALWAYS follow maintenance instructions in this manual for your safety and to prevent damage to the System. ALWAYS power down the GENOSYL DS Console when not in use. DO NOT sterilize (e.g., autoclave, gas sterilize) any of the components of the System, as this may compromise performance. DO NOT use harsh cleaning agents. Doing so may impair the structural integrity and/or function of the device. DO NOT touch or rub the display screen with abrasive cleaning compounds, as they may scratch and damage the screens. ALWAYS ensure the System is completely dry after cleaning before powering it ON. Failure to do so could result in equipment damage.
Switching OFF the System NEVER turn the rear power switch OFF until the System has gone through a controlled shutdown or instructed by VERO Technical Support. Turning the rear power switch OFF prematurely (e.g., while it is still in use) will immediately shut down the device and may cause improper operation upon restart.
Cart DO NOT stand or sit on the Cart. Standing or sitting on the Cart can damage the device. ALWAYS push or pull the Cart using the handle only. NOT doing so may result in damage to the device.

TABLE OF CONTENTS
WARNINGS, CAUTIONS, AND NOTES		3
TABLE OF CONTENTS		11
LIST OF TABLES		13
LIST OF FIGURES		13
ABBREVIATIONS, TERMINOLOGY, AND DEFINITIONS		15
SYMBOLS		17
GENOSYL DS PARTS / COMPONENTS		19
1.	GENERAL INFORMATION	28
1.1	User Responsibility	28
1.2	General Information and Indications for Use	29
1.3	Principles of Operation	30
1.4	Exposure of Healthcare Providers to NO and NO2	34
2.	SYSTEM OVERVIEW	38
2.1	Frequently Used Functions	38
2.2	GENOSYL DS Cart and Consoles	39
2.3	Cassette	45
2.4	GENOSYL DS Ventilator Circuit Components	46
2.5	Gas Lines (detailed explanation)	48
2.6	Console Modes of Operation	50
2.7	Display Screen	50
2.8	Display Menu Tab Navigation	51
2.9	Display Screen Operational Buttons	54
2.10	Display Screen – Cassette Status Indicators	56
2.11	Display Screen - Adaptive Sensor Status	58
2.12	Cassette Insertion into Console	59
2.13	Water Trap / Sample Line Leak Test	60
3.	SYSTEM SET-UP AND CONNECTIONS	64
3.1	GENOSYL DS Set-Up and Mechanical Ventilator Circuit Schematic	64
3.2	Connections to Various Breathing Systems	64
3.2.1	Conventional Ventilators	65
3.2.2	Non-Invasive Gas Delivery Systems	69
3.3	GENOSYL DS Ventilator Circuit Assembly Pre-Check	73
3.4	Assembling GENOSYL DS Injection Assembly with Adaptive Sensor and GENOSYL DS Mixer Assembly with Adaptive Sensor	75
3.4.1	GENOSYL DS Injection Assembly with Adaptive Sensor	75
3.4.2	GENOSYL DS Mixer Assembly with Adaptive Sensor	76
3.5	GENOSYL DS Console Connections	78
3.6	Manual Ventilation (Bag) Connection	83
3.7	Mechanical Ventilator Circuit Connections	84
4.	SYSTEM START UP	88
4.1	Console Start-Up	88
4.2	Cassette Insertion & Water Trap / Sample Line Leak Test	90
5.	NITRIC OXIDE ADMINISTRATION	98
5.1	Nitric Oxide Dose Set-Up and Administration	98
5.2	Adjusting the Dose	101
5.3	Replacement of a Depleted Cassette	103
5.4	Manual Mode	104
5.5	Console Use as a Back-up	108
6.	CONSOLE SHUTDOWN AND CASSETTE DISPOSAL	112
6.1	Console Shutdown	112
6.2	Cassette Disposal	116
7.	USING THE SYSTEM IN THE MR SCANNER ROOM	120
7.1	Connection to the Ventilator Breathing Circuit	120
7.2	Transferring to and from the MR Scanner Room	121
8.	ALARMS, ALERTS, AND TROUBLESHOOTING	126
8.1	Alarms, Alerts, and Troubleshooting	126
8.2	High Priority Alarms and Messages	129
8.3	Medium Priority Alarms and Messages	137
8.4	Low Priority Alarms and Messages	139
8.5	Informational Messages	141
8.6	GaussAlert™ Alarm	142
8.7	Troubleshooting	143
9.	SYSTEM MAINTENANCE	148
9.1	Calibration	148
9.2	Maintenance Schedule	154
9.3	Testing the GaussAlert™ Function	154
9.4	Water Trap Maintenance	156
9.5	Battery	157
9.6	Cleaning	158
10.	MECHANICAL VENTILATION	164
10.1	Mechanical Ventilation	164
10.2	Ventilator Compatibility	166
11	PRODUCT SPECIFICATIONS	172
11.1	System Performance	172
KEY WORD INDEX		184

LIST OF TABLES
Table 1: Conventional Ventilator Compatibility Test Ranges	66
Table 2: Non-Invasive Gas Delivery System Compatibility Test Ranges	69
Table 3: Alarm Icon Descriptions	126
Table 4: Alarm Characteristics	127
Table 5: Alarm Ranges, Defaults and Dose Interruption Condition	127
Table 6: Recommended Cleaning Agents	158
Table 7: Oxygen Dilution	165
Table 8: Compatible Equipment and Accessories	166
Table 9: Details of Validated Systems	168
Table 10: Validated Compatibility with and without Inline Mixer	169

LIST OF FIGURES
Figure 1: GENOSYL DS Console Front Panel	30
Figure 2: Cassette Output Range	31
Figure 3: Calculated Time to Cassette Depletion	32
Figure 4: GENOSYL DS Assembled Cart	40
Figure 5: MR Conditional GENOSYL DS Front View	41
Figure 6: MR Conditional GENOSYL DS Side View	42
Figure 7: Front View GENOSYL DS Console	43
Figure 8: Back View GENOSYL DS Console	44
Figure 9: Right Side View GENOSYL DS Console	44
Figure 10: Left Side View GENOSYL DS Console	44
Figure 11: GENOSYL Cassette	45
Figure 12: GENOSYL DS Gas Lines	49
Figure 13: GENOSYL DS Display Screen	50
Figure 14: Water Trap/Sample Line Leak Test	60
Figure 15: Conventional Ventilator Circuit Set-Up and Connections to the GENOSYL DS and a Manual Bagging System without the Inline Mixer	67
Figure 16: Conventional Ventilator Circuit Set-Up and Connection and a Manual Bagging System with the Inline Mixer	68
Figure 17: Fisher and Paykel Optiflow Jr Breathing Circuit	70
Figure 18: Fisher and Paykel Optiflow Breathing Circuit	71
Figure 19: Infant Bubble CPAP Diagram	72
Figure 20: GENOSYL DS Injection Assembly with Adaptive Sensor	75
Figure 2121: GENOSYL DS Mixer Assembly with Adaptive Sensor	76
Figure 22: MR Scanner Room	122
Figure 23: GaussAlert™ Test	155
Figure 24: Cassette Output Range	166

ABBREVIATIONS, TERMINOLOGY, AND DEFINITIONS
ABBREVIATION / TERMINOLOGY	DEFINITION
DS	Delivery System
Back-up	A situation whereby the Back-up Console and its Cassette is activated in the event of a failure of the Dosing Console.
Cassette	The Cassette contains the material used to make Nitric Oxide and when inserted into the Console is available for dosing the patient.
Display	Electronic information panel located on the front of the Console.
GENOSYL	Nitric Oxide for inhalation
Keypad	A Graphical User Interface function built into the Console display and used to enter the Nitric Oxide dose to be administered to the patient.
L/min	Liters per minute
LPM	Liters per minute
Mixer	Ventilator circuit accessory used to mix the ventilator gas with the gas supplied by the GENOSYL DS for specific ventilator and tidal volume use cases, per Section 10.2.
MRI	Magnetic Resonance Imaging
MR Scanner Bore	The MR scanner opening
MR Exclusion Zone	Area in the MR scanner room where the magnetic field is greater than 100 gauss
MR Scanner	The MR device for diagnostic imaging
MR Scanner Room	The room where the MR scanner is located
NICU	Neonatal Intensive Care Unit
NO	Nitric Oxide
NO Injection Port	Port on the front of the Console that introduces the concentrated NO into the respiratory circuit.
Adaptive Sensor Port	Port on the front on the Console that the Adaptive Sensor Cable plugs into.
Gas Sample Port	Port on the front of the Console at the Water Trap that measures NO, NO2 and O2 levels within the NO gas path prior to reaching the patient.
NO2	Nitrogen Dioxide
O2	Oxygen
ppm	Parts Per Million
Dosing Console	The Console that is actively dosing NO.
Back-up Console	The secondary Console used as a "Back-up" system to administer Nitric Oxide when the Dosing Console cannot be used.
System	The System (GENOSYL DS) consists of a Cart with two Consoles, Cassettes, and component parts used to set up the gas lines
v	Electrical Volts

SYMBOLS
Symbol	Symbol Name	Description
	Magnetic Resonance (MR) Conditional	Indicates that the System has been demonstrated to pose no known hazards in a specified MRI environment with specified conditions of use.
	Magnetic Resonance (MR) unsafe	Keep away from magnetic resonance imaging equipment.
	RF Interference	Devices marked with this symbol may interfere with the Console.
	Water Trap Attachment Point	Indicates the location where the Water Trap with Sample Port is to be attached.
	Unlock position	Direction to push to open the Water Trap.
	Sample Gas Inlet	Attachment point for Sample Line on Water Trap
	NO Injection	Output port for GENOSYL to patient circuit
	Calibration Port	Input port for calibration gas
	Adaptive Sensor Port	Input port for Adaptive Sensor Cable
	Manual Ventilation	Output port for GENOSYL to manual ventilation system
	Operating Instructions	Refer to operating instructions for instructions for use, warnings, precautions, and other equipment information.
	AC	Indicates power input specification is alternating current (AC).
	Ingression	Code for the level of ingression protection tested. The enclosure was tested to be drip proof.
	Catalog or model number	Indicates the catalog number so that the medical device can be identified.
	Batch Code	Indicates the batch code so that the batch or lot can be identified.
	Serial Number	Indicates the serial number so that a specific medical device can be identified.
	Date of Manufacture	Indicates the date when the medical device was manufactured.
	Manufacturer	Indicates the manufacturer of the item.
	Storage humidity range	Indicates the range of humidity to which the medical device can be safely exposed.
	Storage temperature range	Indicates the temperature limits to which the medical device can be safely exposed.
	Atmospheric pressure limitation	To indicate the acceptable upper and lower limits of atmospheric pressure for transport and storage.
	Do not reuse	Indicates a medical device that is intended for one use, or for use on a single patient during a single procedure.
	Attention	Indicates the need for the user to consult the instructions for use for important cautionary information such as warnings and precautions that cannot, for a variety of reasons, be presented on the medical device itself.
	Use by	Indicates the date after which the medical device is not to be used.

GENOSYL DS PARTS / COMPONENTS
PART	PART NAME	VERO BIOTECH PART NUMBER
	GENOSYL DS Console (2 required per System)	602166
	MR Conditional GENOSYL DS System	GENOSYL DS Console (2) 602166 GENOSYL DS Cart 602524 Gauss Alarms Mount (2 gauss alarms installed) 601823
	GENOSYL DS Cart	602524
	Gauss Alarms Mount (2 gauss alarms installed)	601823
	Adaptive Sensor Cable	602489

The following parts are required to set up the GENOSYL DS and deliver Nitric Oxide to the patient breathing circuit, using validated ventilators, ventilator circuits, and manual ventilation equipment.

PART	PART NAME	VERO BIOTECH PART NUMBER
	GENOSYL Cassette	601772
	Adaptive Sensor	602490
	NO Gas Injection Adapter 22M/15F × 22F	601503
	Adapter 22F × 22F	601473
	Inline Breathing Circuit Filter	5003-0015
	GENOSYL DS Mixer	601445
	GENOSYL DS Gas Lines: NO Injection Line (red) Sample Line (blue) Manual Ventilation Line (clear)	601690
	GENOSYL DS Sample Line Extension	601955
	Neonatal Gas Sample Tee	601474
	Water Trap	600896
	22M 22F Elbow Adapter	601746
	Sample Tee, 3/8" Barbed	601970
	Injection Line Filter	601758

The following parts are required to deliver Nitric Oxide using a manual ventilation system.

PART	PART NAME	VERO BIOTECH PART NUMBER
	GENOSYL DS Manual Ventilation Bag NO Adapter	601485

The following parts are required for routine maintenance.

PART		VERO BIOTECH PART NUMBER
	Calibration Gas - 45 ppm NO	601856
	Calibration Gas - 10 ppm NO2	601857
	Calibration Regulator	601860
	Calibration Tee Tubing	601861
	Calibration Extension Tubing	G01436
	Calibration Gas Carrying Case	601859
	Calibration Equipment Wrench	601862

GENOSYL® DS

SECTION 1
GENERAL INFORMATION

1. GENERAL INFORMATION

1.1 User Responsibility

The GENOSYL DS (Console) will perform as described in this Operator's Manual, accompanying inserts, and/or labels when assembled, operated, maintained, and repaired in accordance with the instructions provided. The Console must be set up as described in Section 3. If the Console does not perform as described in Section 3 or during assembly, the parts are found to be broken, missing, contaminated, or visibly worn, they should be replaced immediately.

In the case of repair or replacement of the Console is required, a telephone service request should be made to Technical Support at 877-337-4118. The GENOSYL DS or any of its parts should not be serviced or repaired by anyone other than a VERO Biotech Technical Engineer or without written permission from VERO Biotech Technical Engineering Department.

Any malfunction resulting from faulty maintenance, improper repair, damage, alteration by anyone other than a VERO Biotech Technical Engineer, and/or improper use will be the sole responsibility of the User.

WARNING
The GENOSYL DS must only be used in accordance with the approved indications, usage, contraindications, precautions, and warning described in the GENOSYL DS labeling. Refer to the labeling prior to use.

CAUTION
U.S. Federal law restricts this device to sale by or on the order of a physician. Outside the U.S., check local laws for any restrictions that may apply.

NOTES
Prior to using the GENOSYL DS, read through this Operator's Manual. Follow all instructions and obey the Warnings and Cautions. Keep this Operator's Manual available to readily answer questions. Read through all manufacturer Operator's Manuals for the ventilator, humidifier and any other accessory items used.

1.2 General Information and Indications for Use

GENOSYL DS generates and delivers NO for inhalation at the point of use. The concentration of NO, as set by the user, is monitored, and adjusted to accurately dose the patient throughout an inspired breath. Only validated devices / components should be used with the GENOSYL DS.

The intended population for inhaled NO treatment is term and near-term neonates in neonatal intensive care units (NICUs). Refer to the GENOSYL (nitric oxide) for inhalation drug label for more detailed information.

The GENOSYL DS is intended for use in the hospital and 1.5 Tesla and 3.0 Tesla diagnostic imaging environments.

The GENOSYL DS is intended for use by healthcare professionals (HCPs) who are licensed and actively practicing pediatric and/or neonatal respiratory therapists (RTs) in the United States. These users are required to set up, administer inhaled Nitric Oxide and provide respiratory care (including initiation and maintenance of mechanical ventilators) in the critically ill neonatal population.

The GENOSYL DS starts with liquid N2O4/NO2, which is then converted in a proprietary Cassette to NO. The GENOSYL DS delivers NO into the ventilator stream, where the NO joins a stream of air or O2 and is diluted to the prescribed concentration.

The NO concentration (dose) to be delivered to the patient is selected by the user and is set and maintained independently by means of computer-controlled air pumps, Cassette heaters, and a feedback loop that measures the delivered NO concentration.

The GENOSYL DS takes a gas sample removed from the NO gas flow stream immediately prior to the patient and provides real-time output of the NO, NO2, and O2 concentrations that are being delivered to the patient. The continuous integrated gas monitoring includes a comprehensive alarm system.

The NO concentration detected from the sample line is used in a feedback loop to adjust the NO concentration delivered into the ventilator circuit.

The GENOSYL DS includes a redundant Console for complete Back-up capability for delivery of NO for inhalation. Each Console has a back-up battery that provides at least 1 hour of NO delivery in the absence of an external power source.

1.3 Principles of Operation

GENOSYL DS. The GENOSYL DS continuously introduces a precisely controlled concentration of Nitric Oxide (NO) into the inspiratory limb of the ventilator circuit. GENOSYL DS utilizes the known properties of NO and other oxides of nitrogen, namely dinitrogen tetroxide (N2O4) and nitrogen dioxide (NO2), to create a "tankless" drug/device combination System to produce, at the point of use, ultra-high purity NO for inhalation, providing a consistent, prescribed dose to the patient.

Console. The GENOSYL DS Console contains the electronics to control the production and to maintain the constant and precise delivery of NO.

The primary features of the Console front panel are displayed in Figure 1.

Figure 1: GENOYL DS Console Front Panel

NO generation. The Console uses Cassettes containing liquid N2O4/NO2 inside a stainless-steel vessel (the liquid module) and an antioxidant cartridge. Upon initiation of a Cassette, the liquid N2O4 is heated, producing NO2 gas, which is mixed with up to 0.9 LPM ambient air supplied by the Console. The NO2/air is injected into the antioxidant cartridge inside the Cassette, which converts NO2 to NO.

The Cassette is designed to provide NO in concentrations up to 80 ppm. The maximum and minimum delivered dose for a range of constant inspiratory flow rates is presented in Figure 2.

The maximum combination of dose (ppm) and flow (LPM) output of the System is 800 ppm × LPM (e.g., 20 ppm with 40 LPM, 40 ppm at 20 LPM, etc.). The System is capable of delivering NO at a minimum of 1 ppm × LPM (e.g., 1 ppm at 1 LPM).

Figure 2: Cassette Output Range

The total time to deplete the Cassette N2O4 contents depends on the rate of use. The minimum time to depletion based on use rate is shown in Figure 3. The calculated minimum remaining contents at the current output rate is indicated by a gauge presented on the Console display during use.

Figure 3: Calculated Time to Cassette Depletion

NO Injection into the Ventilator Circuit. After NO is produced in the Cassette, the NO injector introduces the concentrated NO into the ventilator circuit where the NO is diluted to the prescribed concentration (dose) and mixed with the O2 or air supplied to the patient.

Before the gas mixture reaches the patient, a sample line removes a small gas sample and sends it back to the Console, where gas sensors continuously measure the supplied NO, NO2 and O2. The Console software then compares the measured NO concentration to the set NO concentration and continuously adjusts the delivery of NO to maintain the prescribed NO concentration (dose) delivered to the patient (closed loop control). The Console software commands the NO injection flow rate into the ventilator circuit with a maximum flow rate of 0.9 LPM. Changes in the ventilator settings by the user may cause brief transient changes in the measured NO value. The Console software will adjust the injected flow rate and the internal temperature of the Cassette to compensate for the changes in the total ventilator flow rate. For example, a higher minute ventilation will require a higher injection flow rate to produce the same NO concentration.

Mixer. An inline Mixer is used in the applicable ventilator circuit after the NO injection site and before the gas sample site to mix NO from the Console with the gas supplied by the ventilator, for specific ventilator and tidal volume use cases per Section 10.2.

Gas Monitoring. The gas mixture delivered to the patient by the GENOSYL DS is continuously monitored with two NO detectors, with one providing redundant back-up, as well as a detector for NO2 and O2. A sample of inspired gas is taken from the inspiratory limb, close to the patient, and is measured by the gas sensor within the Console. The gas monitoring sensors are electrochemical; they are specific to each gas and provide an electronic signal that is proportional to the concentration of gas present.

Adaptive Sensor. The Adaptive Sensor is used to detect flow in the patient breathing circuit. When flow is not detected by the Adaptive Sensor, Nitric Oxide delivery will be interrupted until flow is detected. The Console will provide a visual and audible high priority alarm when flow is not detected to alert the user (see Section 8.2). Once flow is detected, the Console will auto resume delivery of nitric oxide at the previously set dose. An Adaptive Sensor is recommended for use with certain breathing devices. Refer to Section 3 for recommended set up diagrams. The GENOSYL DS will properly deliver and control Nitric Oxide dose in the absence of an Adaptive Sensor.

Alarms and Dosing Safeguard Fallback Modes. The GENOSYL DS alerts the user in the event of excursions of NO, NO2, and Oxygen from their expected ranges. Nitric Oxide delivery interruption conditions are as follows:

1. Press the gray "Set" button on the display screen.
2. Enter the prescribed dose in ppm on the electronic keypad.
3. Press OK to confirm the entry.
1. Press the gray "Set" button on the display screen.
2. Confirm Total Flow Range is appropriately selected.
3. Enter the prescribed dose in ppm on the electronic keypad.
4. Press OK to confirm the entry.
1. Press the gray "Set" button to access the electronic keypad on the display screen on the Dosing Console.
2. Enter the prescribed dose using the electronic keypad.
3. Press "OK" to confirm the dose and to start dosing administration.
1. Press the gray "Set" button to access the electronic keypad on the display screen on the Dosing Console.
2. Enter the prescribed ppm dose using the numeric keypad.
3. Adjust Total Flow Range, if necessary.
4. Press "OK" to confirm the dose and to start dosing administration.
1. Follow onscreen instructions to replace Cassette.
1. Ensure the oxygen flow source is set appropriately or adjust as needed.
2. Press the button "Switch to Manual" on the Dosing Console.
3. Press Confirm to switch to Manual Dosing.
4. To resume primary dosing, see Section 5.4.3.
1. Navigate to the Settings Tab.
2. Select the Flow Rate from the drop-down menu.
1. Press the "Switch to Primary" button at the top of the Manual Mode screen.
2. Press "Confirm" to start dosing or "Cancel" to cancel.
1. Press the "Set" button on the Back-up Console which will display the NO dose electronic keypad and Flow Selection menu.
2. Confirm Dose and Total Flow range is appropriately selected.
3. Press "OK" to confirm entry
1. Press the gray "Set" button to access the electronic keypad on the display screen.
2. Set the dose to "0" using the electronic keypad.
3. Press "OK" to confirm the entry.
4. If the Settings Tab is not displayed, press the "Menu" tab to access the sub-level tabs.
5. Press the "Settings" tab on the display menu.
6. Press the red "System Shutdown" icon.
7. Press "Confirm" to confirm shutdown.
8. Wait until the Console shuts down, the display screen appears blank, and the Console emits an audible beep.
9. Open the Cassette Access Door.
10. Remove the Cassettes by pulling the Cassette straight out.
11. Dispose the inerted Cassettes per hospital policy.
12. Press the Black Rocker Power Switch to the "OFF" position.
13. Repeat steps 1-12 for the other Console.
1. Check to make sure nothing is connected to the CAL port during Air Calibration.
2. If the Calibration Tab is not displayed, press the "Menu" tab to access the sub-level tabs.
3. Press the "Calibration" tab on the display menu.
4. Press the Low Range "Air" button.
5. Press the blue "Start Calibration" button.
6. Press "OK" to continue once calibration is complete.
1. If the Calibration Tab is not displayed, press the "Menu" tab to access the sub-level tabs.
2. Press the "Calibration" tab on the display menu.
3. Press the High Range "NO" button.
4. Press the gray "Start Calibration" button.
5. Follow the onscreen instructions.
6. Follow the onscreen instructions
7. Press "Accept" to continue once calibration is complete.
1. If the Calibration Tab is not displayed, press the "Menu" tab to access the sub-level tabs.
2. Press the "Calibration" tab on the display menu.
3. Press the High Range "NO2" button.
4. Press the gray "Start Calibration" button.
5. Follow the onscreen instructions.
6. Follow the onscreen instructions.
7. Press "OK" once calibration is complete.
1. Place the test magnet tool on the GaussAlert™ alarm bracket in the area identified in Figure 23.
2. The alarm will activate and a short flash (less than two seconds) of the LED indicates proper function.
3. Move the test magnet tool away from the GaussAlert™ until the alarm stops sounding.
4. Repeat this procedure on the second GaussAlert™.
1. Remove Water Trap from Console by lifting latch and pulling the base of the Water Trap away from the Console.
2. Remove the lid by pulling the lid from the base.
3. Empty the liquid contents.
4. Reattach the lid by pushing it back onto base.
5. Slide the Water Trap back on the Console until it clicks into place.
1. Remove old Water Trap from Console by lifting the latch and pulling the base of the Water Trap away from the Console.
2. Slide new Water Trap back on the Console until it clicks into place. Replace sample line to Water Trap.
3. Discard the old Water Trap.

WARNING
NEVER use the MR Unsafe GENOSYL DS Cart in the MR scanner room. ALWAYS verify at least one gauss alarm is functioning properly prior to use in the MR environment.

CAUTION
ALWAYS operate the Console on a level surface to avoid potential interruption to Nitric Oxide (NO) delivery. DO NOT stand or sit on the Cart. Standing or sitting on the Cart can damage device. ALWAYS push or pull the Cart using the handle only. NOT doing so may result in damage to the device.

NOTE
A System has a top and bottom Console. Both Consoles will start-up in Primary Mode. One Console will be used for dosing and the other will remain in Primary Mode as a Back-up Console. (See Section 5.5)

CAUTION
DO NOT remove Cassette from packaging until ready to use. External packaging is designed to protect the Cassette from damage and/or contamination.

PART	PART NAME	FUNCTION
	NO Gas Injection Adapter 22M/15F × 22F	Used between the Adapter and the Mechanical Ventilator Inspiratory Outlet, and to connect to the NO Injection Line (red).
	Injection Line Filter	Used to filter air from the Injection Line.
	Adaptive Sensor	Used to measure flow from the ventilator into the circuit.
	Adaptive Sensor Cable	Used to communicate flow readings to the Console.
	GENOSYL DS Gas Lines NO Injection Line (red) Sample Line (blue) NO Manual Ventilation Line (clear)	Used to deliver Nitric Oxide to the ventilator circuit and manual ventilation bag, and to sample gas within the ventilator circuit.
	GENOSYL DS Sample Line Extension	Used when the distance between the patient and the DS exceeds the length of the standard sample gas line in the MR Environment.
	Neonatal Gas Sample Tee	Used to connect the Sample Line to the ventilator circuit.
	GENOSYL DS Mixer	Used to mix the NO gas with the gas supplied by the ventilator through a filter containing silica gel to provide intra-breath NO delivery for certain scenarios.
	Adapter 22F × 22F	Used as a coupler between the Mixer and the Gas Injection Adapter when a mixer is required.
	Inline Breathing Circuit Filter	Used to filter air from the Injection Line.
	Sample Tee, 3/8" Barbed	Used to accommodate gas sampling in some ventilator circuits, (e.g., Crossvent Infant Circuit).
	GENOSYL DS Manual Ventilation Bag NO Adapter	Used to connect oxygen tubing to manual ventilation bagging system to deliver nitric oxide. Includes an NO Injection Port to connect to the NO Injection Line.
	Water Trap	Used to protect sample system by collecting condensation and filtering contaminants from the sampled gas. The Water Trap may need to be emptied or changed while in use (refer to Section 9.4).

MODE	FUNCTIONAL CHARACTERISTICS
Primary	The mode of operation for controlled dosing with Smart Feedback System™.
Manual	The mode of operation used for manual ventilation. Manually adjustable fixed dosing without the need of feedback for certain conditions.

NOTE
Some confirmation display screens (e.g., "Confirm", "Yes", "Accept", etc.) will be semi-transparent after dosing has been initiated to allow the Operator to continue to see important information on the underlying screen (e.g., NO values, Alarms, Alerts, etc.).

MENU TAB DISPLAY	TAB / BUTTON	DESCRIPTION
		Press this tab to access the sub-level tabs (Main, Alarms, Calibration, Events, and Settings).
		Displayed when the Alarms Tab is selected, this screen is used to set the Upper and Lower Alarm Limits for NO (ppm), NO2 (ppm), and O2 (%). A list of Alarms that have occurred since the last reset for the Console will be displayed on this tab.
NOTE
See Section 8 for additional information on alarms and alerts.
	Displayed after pressing the Alarms tab, press this button to switch to the default upper and lower limits for NO (ppm), NO2 (ppm), and O2 (%).
	Pressing this button will clear the alarm history from the alarm log visible on this tab. The alarm will remain logged in the Console's permanent logs.
	Press this tab to return to the main screen. Pressing the Main Tab will collapse the tab menu.
		Press this tab to access the calibration screen.
NOTE
See Section 9.1 for additional information on Calibration.
	Press this button to calibrate the low range of the NO and NO2 sensor.
	Press this button to calibrate the high range for the NO sensor.
	Press this button to calibrate the high range for the NO2 sensor.
	Press this button to initiate calibration for the selected gas.
	Press this button to stop the calibration in the middle of a calibration process. The previous calibration will remain to be used.
	Press this button to display the history of calibration.
		Press this tab to access the events menu.
	Press this button to clear the events listed on the events screen.
		Press this tab to access the settings screen.
	Press this button to begin the process of shutting down the Console.
	Press this button to switch display to day mode.
	This drop-down menu allows operator to preset the dilution flow rate for Manual Mode. If no rate is selected, Console will default to 10 LPM.
	Press this button to enter the screen to adjust the date and time. This button is only present when logged as an Administrator
	Press this button to adjust the date and time. This button is only present when logged as an Administrator
	Press this button to perform a Water Trap/ Sample Line Leak Test.
	Used by service personnel only. Password controlled.
NOTE
Call Technical Support at 877-337-4118 for additional support.
	Press this button to display a window to enter date ranges to retrieve dosing usage over a period of time and number of Cassette activations.
		Day Mode Main Menu: Press this tab to access the sub-level tabs (Main, Alarms, Calibration, Events, and Settings).
	Press this button to switch display from day mode to regular mode.

BUTTON	DESCRIPTION
	Press this button to set the targeted NO (ppm) dose when in Primary Mode.
	Press this button to pre-silence alarms. Pushing this button will pre-silence specific alarms for 120 seconds. When active, a red "X" will appear through the alarm icon with a countdown of how much longer alarms will be pre-silenced for. When tapping the icon with the red "X", the user will cancel the pre-silence.
	Press this button to cancel the Water Trap / Sample Line Leak Test.
	Press this button to switch a Console to Primary Mode from Manual Mode. When in Primary Mode, the dosage can be set to a user selected (prescribed) level.
	Press this button to switch from Primary Mode to Manual Mode. See Section 5.4 for information about dosing in Manual Mode.
	Electronic keypad used to set and adjust the prescribed targeted Nitric Oxide dose to be delivered to the patient. Includes buttons to confirm (OK), cancel, or clear the entry.
	The Total Flow Range is selected by the user if the Adaptive Sensor is not connected to the Console. These buttons will only appear if the Console does not detect an Adaptive Sensor when setting or adjusting dose. Total Flow range is the sum of the ventilator (or ancillary equipment) Bias Flow and the minute ventilation of the patient.
	Displayed when in Manual Mode, press the green up or down arrows to adjust the dose to the patient, from the default dose. Pressing the down arrow will decrease the dose in increments of 1 ppm for 24 ppm and below. Pressing the up arrow will increase the dose in increments of 2 ppm above 24 ppm. Press the green LPM (liters per minute) button to activate a drop-down menu and set a different dilution flow rate.
	Press this button to confirm the action specified on the screen.
	Press this button to cancel the action specified on the screen.
	Press this button to acknowledge the information message displayed on the screen.
	Press this button to move to the next step.
	Press this button to cancel the current step.

CASSETTE DISPLAY	DESCRIPTION
	This Cassette Status Indicator will be displayed when a Cassette is not loaded into the Console. The Cassette Status Indicator will display "REPLACE" and will alternate between a dark red and light red. The user is prompted to "Replace"
	This Cassette Status Indicator is displayed during the warmup phase when a new Cassette is inserted. This Indicator will display "WARMING" alternating with "READY". Dose may be initiated while the Cassette is warming.
	This Cassette Status Indicator is displayed once the Cassette has achieved a fully preheated status.
	This Cassette Status Indicator is displayed during dosing. If a secondary Cassette has been inserted, the Cassette Status Indicator will display "Dosing" for the dosing Cassette and "Ready" for the secondary Cassette. If a secondary Cassette has not been inserted, the Cassette Status Indicator will display the percentage of Nitric Oxide remaining in the dosing Cassette and the secondary Cassette Status Indicator will be red and display "Replace".
	This Cassette Status Indicator will be displayed when the Console is transitioning from the dosing Cassette to the secondary Cassette. The direction of the arrow indicates the Cassette that is being transitioned to.
	This Cassette Status Indicator will be displayed when less than one hour of Cassette life remains and no secondary Cassette is inserted. The indicator will display the percentage of life remaining in the dosing Cassette and the estimated time before depletion. The cassette status indicator for the dosing Cassette will appear yellow and display "Dosing" and the other Cassette Status Indicator will appear red and display "Replace"
	This Cassette Status Indicator is displayed when a Cassette is depleted and no secondary Cassette is inserted in the Console. This status will only display if another Cassette is not present in the Console. The Cassette Status Indicator for the dosing Cassette will appear red and display "Dosing 0%" and "0m". The empty Cassette Status Indicator will appear red and display "Replace". Both indicators will alternate between a dark and light red color.
	This Cassette Status Indicator will be displayed when a Cassette that has previously been used is inserted in a Console. The Cassette display will alternate between "USED" and an "X" through the Cassette icon. The Console will automatically eject a previously used Cassette.

ADAPTIVE SENSOR DISPLAY	DESCRIPTION
	The Console has detected flow through the Adaptive Sensor.
	The Console has detected an Adaptive Sensor without flow. "Flow Not Detected" will be displayed under the dose set button when ventilator flow is not detected. To initiate delivery, the Console requires flow detection. The Set button will not appear until flow is detected through the Adaptive Sensor. The screen will appear as pictured below. Once flow is detected, the set button will appear and allow the user to set the dose.
	The Console does not detect an Adaptive Sensor is connected
	An Adaptive Sensor is detected but the Adaptive Sensor is either malfunctioning or not properly connected to the Adaptive Sensor Cable.

PHOTO	DESCRIPTION
	Insert the Cassette into the receptacle. Push in until you hear the Cassette click into the mechanism.
	The on-screen Cassette Status Indicator will switch to say "READY" and then prompt the user to begin a Water Trap/ Sample Line Leak Test.

TEST IN PROCESS	TEST PASSED

Figure 14: Water Trap/Sample Line Leak Test

NOTE
Naming conventions: The GENOSYL DS accessories and components consist of the GENOSYL Injection Assembly with Adaptive Sensor, (Section 3.4), or the GENOSYL DS Mixer Assembly with Adaptive Sensor (Section 3.5), and the GENOSYL DS Gas Lines (Section 3.6). Refer to Section 10.2 Table 10 for when use of the Mixer Assembly with Adaptive Sensor is recommended. Connections and disposable circuits to breathing Systems may vary and are unique to individual manufacturers. Example circuit diagrams are provided for reference.

WARNING
ALWAYS use the GENOSYL DS in accordance with the indications, usage, contraindications, warnings, and precautions described in the GENOSYL prescribing information and labeling. Refer to latest approved prescribing information and labeling prior to use. The approved patient population for the GENOSYL DS as specified in the drug labeling for GENOSYL (nitric oxide) for inhalation, is limited to neonates. The GENOSYL DS is not intended to be used in other patient populations. ONLY use the GENOSYL DS, its parts, and accessories as instructed. Using non-specified components may result in product malfunction, injury or death. ALWAYS follow pre-use setup instructions for the routing and connections of tubing to avoid patient strangulation. MAKE SURE the System has all tubing connected as described in the instructions. Not connecting all tubing may result in inaccurate dosage and harm to the patient. DO NOT use accessories or cables other than those specified or provided by the manufacturer of this equipment, as this may result in increased electromagnetic emissions or decreased electromagnetic immunity of this equipment and result in improper operation.

CAUTION
Prolonged use in dry environments without humidification will damage the gas sensors. Supplemental humidification providing greater than 20% relative humidity (RH) in the patient circuit is recommended.

NOTE
All circuit components, including GENOSYL DS circuit components, should be changed out and disposed of according to hospital protocol.

WARNING
ONLY use the GENOSYL DS with Bio-Med Crossvent 2+/2i+ with Constant Flow ON. Not doing so may lead to elevated NO2 levels or dose variability.

NOTE
Use with Compliance Compensation OFF is recommended in the presence of a deliberate leak, per the Servo-I User Manual. With Compliance Compensation ON, the sample flow from the GENOSYL DS may cause a leak detection alarm to trigger for the lowest potential ventilator flows. For use with Hamilton C2/C3 at pediatric/adult ventilator settings, it is recommended that the 2.5 to 10 LPM Total Flow setting be used for Nitric Oxide dosing, when not using an Adaptive Sensor.

Table 2: Non-Invasive Gas Delivery System Compatibility Test Ranges
Setting	Range	Unit
Optiflow Jr Flow Rate	0.75-36	LPM
Optiflow Flow Rate	3-60	LPM
Bubble CPAP Continuous Flow Rate	4-15	LPM
CPAP Pressure	3-10	cmH2O

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
Cassettes – 2 ea. Adaptive Sensor – 1 ea. Adaptive Sensor Cable – 1 ea. Gas Injection Adapter – 1 ea. Inline Breathing Circuit Filter 1ea. Mixer Assembly Mixer – 1 ea. Adapter (22mm ID × 22mm ID) – 1ea. Inline Breathing Circuit Filter– 1 ea. Gas Lines – 1 ea. Gas Sample Tee – 1 ea. Manual Ventilation Bag NO Adapter – 1 ea.	1. Remove all items of the GENOSYL DS Parts / Components from packaging. 2. Check the expiration date for each Cassette and the Inline Breathing Circuit Filter (if Mixer Assembly is used) to ensure use is within the expiration date.	WARNING
DO NOT use a Cassette that is beyond its expiration date. Using an expired Cassette may affect the Cassette's ability to provide the correct NO dosage to the patient, which may cause injury or death.
NOTE
A Mixer Assembly is not required for all use cases. Refer to Section 10.2, Table 10)
	3. Visually inspect the Water Traps on both Consoles to ensure they are installed and empty.	WARNING
ALWAYS empty Water Trap before each use, when prompted by the System, and when the trap is more than half full. Allowing the Water Trap to completely fill will occlude the Sample Line which will interrupt patient gas NO, NO2, and O2 concentration monitoring. Failure to monitor the patient gas NO, NO2, and O2 concentrations may result in patient injury. ALWAYS conduct Water Trap/ Sample Line Leak Test every time you empty and replace the Water Trap, as failure to do so may lead to an incorrect NO reading, which can result in injury or death.
NOTE
To empty the Water Trap, see Section 9.4.1

NOTE
When using a Mixer, an Inline Breathing Circuit Filter must be used. If a Mixer is not used, an Inline Breathing Circuit Filter as presented in Figure 20 may be used, or an Injection Line Filter connected to the port on the Gas Injection Adapter may be used.

ILLUSTRATION	ACTION
	1. Connect the Inline Breathing Circuit Filter to the Gas Injection Adapter (22 mm ID × 22 mm OD).
	2. Connect the Adaptive Sensor to the inlet end of Gas Injection Adapter (22mm ID × 22 MM OD).

ILLUSTRATION	ACTION
	1. Connect the Inline Breathing Circuit Filter to the Gas Injection Adapter 22mm ID × 22 mm OD.
	2. Connect the Adapter (22mm ID × 22 mm ID) to the distal end of the Mixer.
	3. Connect the Gas Injection Adapter to the proximal end of the Mixer.
	4. Connect the Adaptive Sensor to the proximal end of the Gas Injection Adaptor

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Push and twist clockwise the short Y-end of the NO Injection Line (red) to the "NO" port (red) on the front panel of the top Console.
	2. Push and twist the short Y-end of the Sample Line (blue) to the Gas Sample Port (blue) on the front of the Water Trap, attached to the top Console.	NOTE
Ensure the Sample Lines are connected to the Water Traps on both Consoles.
	3. Push and twist clockwise the end of the Manual Ventilation Line (clear) to the Manual Ventilation Port (clear) on the front panel of the top Console 4. Repeat steps 1, 2, and 3 on the bottom Console.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Connect the Adaptive Sensor Cable to the Adaptive Sensor Port on front of the Dosing Console.	NOTE
The Adaptive Sensor should only be connected to the Dosing Console.

INSTRUCTIONS FOR USE

TABLE OF CONTENTS
TABLE OF CONTENTS		2
LIST OF TABLES		3
LIST OF FIGURES		3
1.	SYSTEM SET-UP AND CONNECTIONS	5
1.1.	GENOSYL DS Set-Up and Mechanical Ventilator Circuit Schematic	5
1.2.	Connections to Various Breathing Systems	7
1.3	GENOSYL DS Ventilator Circuit Assembly Pre-Check	12
1.4	Assembling GENOSYL DS Injection Assembly with Adaptive Sensor	13
1.4.1	GENOSYL DS Injection Assembly with Adaptive Sensor	13
1.4.2	GENOSYL DS Mixer Assembly with Adaptive Sensor	13
1.5	GENOSYL DS Console Connections	14
1.6	Manual Ventilation (Bag) Connection	18
1.7	Mechanical Ventilator Circuit Connections	18
2	SYSTEM START UP	19
2.1	Console Start-Up	19
2.2	Cassette Insertion & Water Trap / Sample Line Leak Test	20
3	NITRIC OXIDE ADMINISTRATION	21
3.1	Cassette Activation	21
3.2	Nitric Oxide Dose Set-Up and Administration	21
3.3	Replacement of a Depleted Cassette	22
3.4	Manual Mode	23
3.5	Resuming Primary Dosing	24
3.6	Adjusting the Dose	24
3.7	Console Use as a Back-Up	24
4	CONSOLE SHUTDOWN AND CASSETTE DISPOSAL	25
4.1	Console Shutdown	25
4.2	Cassette Disposal	27
5	ALARMS, ALERTS, AND TROUBLESHOOTING	27
5.1	Alarms, Alerts, and Troubleshooting	27
6	MAINTENANCE	28
6.1	Calibration	28
6.2	Maintenance Schedule	30
6.3	Water Trap Maintenance	31
6.4	Battery	32
6.5	Cleaning	32
6.6	Storage	33
6.7	Ventilator Compatibility	34

LIST OF TABLES
Table 1: Conventional Ventilator Compatibility Test Ranges	7
Table 2: Non-Invasive Gas Delivery System Compatibility Test Ranges	9
Table 3: Compatible Equipment and Accessories	34
Table 4: Details of Validated Systems	36
Table 5: Validated Compatibility with and without Inline Mixer	37

LIST OF FIGURES
Figure 1: Front View GENOSYL DS Console	4
Figure 2: GENOSYL DS Display Screen	5
Figure 3: Conventional Ventilator Circuit Set-Up and Connections to the GENOSYL DS and a Manual Bagging System with Injection Assembly with Adaptive Sensor	8
Figure 4: Conventional Ventilator Circuit Set-Up and Connection to the GENOSYL DS and a Manual Bagging System with the Mixer Assembly with Adaptive Sensor	8
Figure 5: Fisher and Paykel Optiflow Jr Breathing Circuit Diagram	10
Figure 6: Fisher and Paykel Optiflow Breathing Circuit	10
Figure 7: Infant Bubble CPAP Diagram	11
Figure 8: GENOSYL DS Injection Assembly with Adaptive Sensor	13
Figure 9: GENOSYL DS Mixer Assembly with Adaptive Sensor	14
Figure 10: Manual Ventilation System	18

Figure 1: Front View GENOSYL DS Console

Figure 2: GENOSYL DS Display Screen

1. SYSTEM SET-UP AND CONNECTIONS

1.1. GENOSYL DS Set-Up and Mechanical Ventilator Circuit Schematic

NOTE: Naming conventions: The GENOSYL DS accessories and components consist of the GENOSYL Injection Assembly with Adaptive Sensor or GENOSYL DS Mixer Assembly with Adaptive Sensor, and the GENOSYL DS Gas Lines. Refer to Section 6.7 Table 5 for when use of the Mixer Assembly with Adaptive Sensor is recommended.

NOTE: All circuit components, including GENOSYL DS circuit components, should be changed out according to hospital protocol.

WARNING:

ALWAYS use the GENOSYL DS in accordance with the indications, usage, contraindications, warnings, and precautions described in the GENOSYL prescribing information and labeling. Refer to latest approved prescribing information and labeling prior to use.
The approved patient population for the GENOSYL DS as specified in the drug labeling for GENOSYL (nitric oxide) for inhalation, is limited to neonates. The GENOSYL DS is not intended to be used in other patient populations.
ONLY use the GENOSYL DS, its parts, and accessories as instructed. Using non-specified components may result in product malfunction, injury or death.
ALWAYS follow pre-use setup instructions for the routing and connections of tubing to avoid patient strangulation.
MAKE SURE the System has all tubing connected as described in the instructions. Not connecting all tubing may result in inaccurate dosage and harm to the patient.
DO NOT use accessories or cables other than those specified or provided by the manufacturer of this equipment, as this may result in increased electromagnetic emissions or decreased electromagnetic immunity of this equipment and result in improper operation.

1.2. Connections to Various Breathing Systems

1.2.1. Conventional Ventilators

Bio-Med Devices CrossVent 2+/2i+
Bio-Med Device MVP-10
Dräger V500
Dräger VN500
GE Healthcare R860
Hamilton C1/T1
Hamilton C2/C3
Hamilton G5
Hamilton MR1
Maquet Servo-U/N/I
Maquet Servo-I MR
Puritan Bennett 840
Puritan Bennett 980
Vyaire AVEA

WARNING: ONLY use the GENOSYL DS with Bio-Med Crossvent 2+/2i+ with Constant Flow ON. Not doing so may lead to elevated NO2 levels or dose variability.

Table 1: Conventional Ventilator Compatibility Test Ranges
Setting	Range	Unit
Inspiratory Flow Rate	2-120	LPM
Respiratory Rate	6-60	BPM
Peak Inspiratory Pressure	0-70	cmH2O
PEEP	0-20	cmH2O

For applicable use scenarios, and when use of a mixer is required, see Section 6.7, Table 5.

Figure 3: Conventional Ventilator Circuit Set-Up and Connections to the GENOSYL DS and a Manual Bagging System with Injection Assembly with Adaptive Sensor

Figure 4: Conventional Ventilator Circuit Set-Up and Connection to the GENOSYL DS and a Manual Bagging System with the Mixer Assembly with Adaptive Sensor

1.2.2 Non-Invasive Gas Delivery Systems

Fisher and Paykel Optiflow Jr Breathing Circuit
Fisher and Paykel Optiflow Breathing Circuit
Infant Bubble Continuous Positive Airway Pressure (CPAP)

Table 2: Non-Invasive Gas Delivery System Compatibility Test Ranges
Setting	Range	Unit
Fisher and Paykel Optiflow Jr Breathing Circuit	0.75-36	LPM
Fisher and Paykel Optiflow Breathing Circuit	3-60	LPM
Bubble CPAP Continuous Flow Rate	4-15	LPM
CPAP Pressure	3-10	cmH2O

For applicable use scenarios, see Section 6.7, Table 5.

Figure 5: Fisher and Paykel Optiflow Jr Breathing Circuit Diagram

Figure 6: Fisher and Paykel Optiflow Breathing Circuit

Figure 7: Infant Bubble CPAP Diagram

1.3 GENOSYL DS Ventilator Circuit Assembly Pre-Check

Follow the steps listed below for the initial System pre-check prior to completing the ventilator circuit assembly.

1. Remove all items of the GENOSYL DS Parts / Components from packaging.

2. Check the expiration date for each Cassette and Inline Breathing Circuit Filter(if Mixer assembly is used) to ensure use is within the expiration date.

WARNING: DO NOT use a Cassette that is beyond its expiration date. Using an expired Cassette may affect the Cassette's ability to provide the correct NO dosage to the patient, which may cause injury or death.

3. Visually inspect the Water Traps on both Consoles to ensure they are installed and empty (Note: To empty the Water Trap, see Section 6.3.1).

WARNING:

ALWAYS empty Water Trap before each use, when prompted by the System, and when the trap is more than half full. Allowing the Water Trap to completely fill will occlude the Sample Line which will interrupt patient gas NO, NO2, and O2 concentration monitoring. Failure to monitor the patient gas NO, NO2, and O2 concentrations may result in patient injury.
ALWAYS conduct Water Trap/Sample Line Leak Test every time you empty and replace the Water Trap, as failure to do so may lead to an incorrect NO reading, which can result in injury or death.

1.4 Assembling GENOSYL DS Injection Assembly with Adaptive Sensor

The Injection Assembly with Adaptive Sensor or the Mixer Assembly with Adaptive Sensor is the point of Nitric Oxide injection into the patient respiratory circuit. Only one type assembly is required for each patient circuit. For certain scenarios, the Mixer Assembly with Adaptive Sensor is recommended to mix the NO gas with the gas supplied by the ventilator through a filter containing silica gel to provide intra-breath NO delivery. Refer to Table 5 for scenarios when a Mixer is recommended for use.

NOTE: When using a Mixer, an Inline Breathing Circuit Filter must be used. If a Mixer is not used, an Inline Breathing Circuit Filter as presented in Figure 8 may be used, or an Injection Line Filter connected to the port on the Gas Injection Adapter may be used.

1.4.1 GENOSYL DS Injection Assembly with Adaptive Sensor

Connect the Inline Breathing Circuit Filter to the Gas Injection Adapter (22mm ID × 22 mm OD).
Connect Adaptive Sensor to the inlet end of Gas Injection Adapter.

Figure 8: GENOSYL DS Injection Assembly with Adaptive Sensor

1.4.2 GENOSYL DS Mixer Assembly with Adaptive Sensor

1. Connect the Inline Breathing Circuit Filter to the Gas Injection Adapter (22mm ID × 22 mm OD). 2. Connect the Gas Injection Adapter (22mm ID × 22 mm OD) to the distal end of the Mixer. 3. Connect the Gas Injection Adapter to the proximal end of the Mixer.
4. Connect Adaptive Sensor to the proximal end of the Gas Injection Adapter.	NOTE: Ensure the Sample Lines are connected to the Water Traps on both Consoles.

Figure 9: GENOSYL DS Mixer Assembly with Adaptive Sensor

NOTE: To determine if the Injection Assembly with Adaptive Sensor or the Mixer Assembly with Adaptive Sensor is recommended, see Section 6.7, Table 5.

1.5 GENOSYL DS Console Connections

1.5.1 GENOSYL DS Gas Lines Connections

Follow the steps listed below to connect the Gas Lines to both Consoles.

1. Push and twist clockwise the short Y-end of the NO Injection Line (red) to the "NO" port on the front panel of the top Console.

2. Push and twist the short Y-end of the Sample Line (blue) to the Gas Sample Port on the front of the Water Trap, attached to the top Console.

NOTE: Ensure the Sample Lines are connected to the Water Traps on both Consoles.

3. Push and twist the short Y-end of the Manual Ventilation Line (clear) to the Manual Bagging Port on the front of the top Console.

4. Repeat steps 1, 2, and 3 on the bottom Console.

5. Connect Adaptive Sensor Cable to Adaptive Sensor Port on front of the Primary Console.

1.5.2 GENOSYL DS Sample Line Extension Connection

For use in the MR Environment when a longer sample line may be required, follow the steps listed below to connect a Sample Line Extension. It is recommended to install the extension prior to initiation of dose.

	1. If actively dosing, switch to Manual prior to completing the following steps.
	WARNING: Failure to switch to Manual Mode prior to installing a Sample Line Extension when the System is actively dosing may result in a spike in the NO dose delivered to the patient.
	2. Turn the blue Stopcock Valve, attached at the Gas Sample Tee, to the closed position as shown.
	2. Push and twist counterclockwise the Luer-Lock Collar of the Sample Line to remove from the blue Stopcock Valve at the Gas Sample Tee.
	3. Push and twist clockwise the Luer-Lock Collar of the Sample Line onto the Sample Line Extension female connection. 4. Push and twist clockwise the Luer-Lock Collar of the Sample Line onto the blue Stopcock Valve at the Gas Sample Tee. 5. Perform Water Trap/Sample Line Leak test, as instructed.
	6. If actively dosing, switch back to Primary Mode

1.5.3 GENOSYL DS Respiratory Circuit Connections

Follow the steps listed below to connect the Gas Lines to the Injection Assembly, Sample Tee, and Adaptive Sensor. If a Sample Tee already exists within the ventilator circuit, the Sample Line may be connected directly to the existing Sample Tee.

	1. Push and twist clockwise the Luer-Lock Collar from the NO Injection Line onto the NO Injection Assembly.
	NOTE: After connecting, the valve assembly may have rotated such that the orientation may appear different from what is shown here and on the display screen.
	2. Push and twist clockwise the Luer-Lock Collar of the Sample Line onto the Sampling Port of the Gas Sample Tee.
	NOTE: Skip this step if a Gas Sample Tee is already connected and in-line with the ventilator circuit.
	3. Ensure the blue Stopcock Valve is in the open position as shown.
	4. Connect the distal end of the Adaptive Sensor Cable to the Adaptive Sensor on the Injection Assembly

1.6.1 Manual Ventilation (Bag) Connection

Figure 10: Manual Ventilation System

1. Attach the barbed end of the Manual Ventilation Bag NO Adapter into the oxygen tubing from the oxygen source.

2. Attach the other end of the NO Adapter to the oxygen port on the side of the Manual Ventilation Bag.

3. Connect the Manual Ventilation Line (clear) to the NO Injection Port of the Manual Ventilation Bag NO Adapter.

4. Place the Manual Ventilation Assembly in a clean accessible place if needed for future use.

1.7 Mechanical Ventilator Circuit Connections

Follow the steps outlined in this section to connect the GENOSYL DS Ventilator Circuit Assembly to the Mechanical Ventilator Circuit.

WARNING:

ALWAYS ensure the trigger sensitivity of the ventilator is checked after connecting the GENOSYL DS to the breathing circuit. The GENOSYL DS injects and samples gas from the patient respiratory circuit which may affect the triggering sensitivity of the ventilator.
ALWAYS ensure the patient disconnect and high–pressure alarms are used with the ventilator. Otherwise, the System is not working properly.

NOTE: All ventilator connections should be assembled and inspected prior to connecting to the mechanical ventilator circuit.

Disconnect the Inspiratory Tubing from the humidifier and attach it to the proximal end of the Injection Assembly to the Adaptive Sensor.
Attach the distal end of the Injection Assembly to the humidifier.
Insert the Sample Tee into the ventilator circuit at the proximal end of the temperature probe closest to the patient.

2 SYSTEM START UP

2.1 Console Start-Up

CAUTION:

ONLY use the GENOSYL DS with the power cord supplied by the manufacturer. Use of a generic power cord may cause output voltage instability leading to a touch screen failure.
ALWAYS ensure the power cord is firmly seated into the power supply and the wall outlet. A loose connection can result in damage to the device or faulty operation.

Push the Circular Power Connectors into the back of the top and bottom Consoles.
Connect the main power cord to a grounded 120 V electrical outlet.
Press the Black Rocker Power Switch, located on the back of each Console, to the right (ON position) to power on both Consoles.
Press the Silver Power Button, located at the top left corner on the front panel of each Console, to turn on the display screens on both Consoles. The display screen will illuminate, and the Consoles will beep, indicating the power is on.

CAUTION: The System will conduct an internal self-test. If an alarm or failure message should occur, refer to Section 8 in the Operator's Manual to resolve the issue.

NOTE: If the display screen does not turn on, see Troubleshooting, Section 8 of the Operator's Manual.

2.2 Cassette Insertion & Water Trap / Sample Line Leak Test

The following steps should be taken on both the top and bottom Consoles. Upon the insertion of the Cassette, a test will be initiated on each Console to check and ensure the integrity of the Water Traps and Sample Line.

The Water Trap / Sample Line Leak Test is automatically initiated when a Cassette has been inserted, and the measured NO is less than 1.0 ppm.

WARNING: ALWAYS follow Cassette insertion instructions prior to Cassette insertion. Not inspecting the Cassette prior to insertion may lead to using a faulty Cassette, resulting in injury.

1. Confirm the Cassette State Window on each Cassette is blue.

WARNING: DO NOT use the Cassette if the Cassette State Window is not blue. A Cassette State Window that is any color other than blue may affect the Cassette's ability to provide the correct NO dosage to the patient, which may cause injury or death.

NOTE: If the Cassette State Window is not blue, see Troubleshooting, Section 8.7 of the Operator's Manual.

2. Open the Cassette Access Doors and insert two Cassettes into the Dosing Console and at least one Cassette into the Back-Up Console. Push until it clicks.

NOTE: The Water Trap / Sample Line Leak Test is automatically initiated when a Cassette has been inserted, and the measured NO is less than 1.0 ppm

After the first Cassette is fully inserted, the Operator will have 60 seconds to close the blue Stopcock Valve to perform the test.

3. Follow the onscreen instructions on both Consoles.

NOTE:

The screen will indicate the Water Trap / Sample Line Leak Test has started and the progress bar will be red until the stopcock valve has been closed, upon which it will then turn green if there is no leak detected.
See Section 3.5 for detail around dosing in Manual Mode.

4. Follow the onscreen instructions on both Consoles.

CAUTION: Open the blue Stopcock Valve prior to pressing "Accept". Failure to do so will result in a line occlusion error.

NOTE: If the Water Trap / Sample Line Leak Test fails, follow the onscreen instructions to resolve the issue. Also see Troubleshooting, Section 8.7 of the Operator's Manual.

If this screen is displayed, follow the onscreen instructions on both Consoles.
Press Yes on both Consoles to begin a new Water Trap / Sample Line Leak Test.

3 NITRIC OXIDE ADMINISTRATION

3.1 Cassette Activation

3.2 Nitric Oxide Dose Set-Up and Administration

WARNING:

MAKE SURE the System stabilizes to the prescribed concentration (ppm) of NO prior to leaving the Console unattended. Failure to do so could result in under delivery of the target NO, leading to injury or harm.
ALWAYS constantly monitor the patient. System malfunctions can occur if device and patient are not monitored and can result in injury or death. Careful monitoring is required by care personnel whenever the System is used on a patient. The use of an alarm and a monitoring system does not give an absolute assurance of warning for every malfunction that may occur. Certain alarms may require immediate response.
If the gas flow of the patient's respiratory device/ventilator should be interrupted or discontinued, the NO dose should be maintained by switching to Manual Mode or the target NO dose should be set to zero.

3.3.1 Setting a dose when using a circuit with an Adaptive Sensor

1. Press the gray "Set" button on the display screen.

2. Enter the prescribed dose in ppm on the electronic keypad.

3. Press OK to confirm the entry.

3.3.2 Setting the dose when using a circuit without an Adaptive Sensor

4. Press the gray "Set" button on the display screen.

5. Confirm Total Flow Range is appropriately selected.

6. Enter the prescribed dose in ppm on the electronic keypad.

7. Press OK to confirm the entry.

NOTE:

The time to reach target dose may vary up to 10 minutes.
If unable to set the dose in Primary Mode, see Troubleshooting, Section 8 of the Operator's Manual.

3.3 Replacement of a Depleted Cassette

The GENOSYL DS automatically switches from the dosing Cassette to the secondary Cassette in the Dosing Console once the Cassette is depleted, when a secondary Cassette is properly inserted and preheated. After transition, the depleted Cassette is automatically ejected.

CAUTION:

User should always have a secondary Cassette inserted in Dosing Console and preheated in order for auto transition to occur. User should replace depleted Cassette as soon as possible after ejection.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
		NOTE
		The Console will automatically transition to the secondary Cassette if properly inserted and preheated. The screen to the left will be displayed during the transition process.

3.4 Manual Mode

NOTE: When entering Manual Mode, the set target dose in primary will carry over to Manual Mode if 5 ppm or greater. Less than 5 ppm set target dose in Primary will default to 5 ppm dose in Manual Mode. However, dose and flow rate be adjusted for specific situations. The feedback loop is disabled while in Manual Mode. To reinitiate the feedback loop, switch back to Primary Mode as soon as the situation permits

3.4.1 Manual Ventilation Use (Bagging)

WARNING:

ALWAYS ensure that the manual flow displayed on the Console matches the flow set into the resuscitation bag. Incorrect flow settings may result in an incorrect estimation of NO delivery. If the flow into the manual equipment is too low, there is risk of overdosing the patient with NO.
ALWAYS squeeze the bag several times, after starting fresh gas flow, to empty residual gas in the bag prior to using the System to ventilate a patient. Failure to do so could result in higher NO2 levels being delivered to the patient.
ALWAYS use the smallest bag adequate to deliver the desired tidal volume. Failure to do so could result in higher NO2 levels being delivered to the patient.
ONLY use a manual resuscitation bag with the GENOSYL DS for a short time (e.g., less than one hour) when on battery only. Otherwise, the System may shut off and may result in injury or death.
If the dilution flow rate displayed on the screen does not match the wall source, then the estimated NO may be inaccurate.

Ensure the oxygen source is set appropriately or adjust as needed.
Press the button "Switch to Manual" on the Primary Console.
Press "Confirm" to switch to Manual Mode
To resume primary dosing, see Section 3.5.

NOTE:

Dosing has been initiated at the default setting of 20 ppm at 10 LPM flow rate, however, these levels may be adjusted.
If the dosing was set at "0" prior to pressing the "Switch to Manual" button, the estimated NO will also be at "0" and will need to be adjusted. If the primary dosing was set between 1 and 5 ppm prior to pressing the "Switch to Manual" button, the estimated NO dose will also be 5 ppm and may be adjusted.
If an adjustment of the NO concentration is required, press the green up and down arrows.
If an adjustment to the Dilution Flow Rate is required, press the LPM value and a drop-down menu will expand. Press the prescribed value. The new value will be highlighted in blue and the drop-down menu will collapse.

3.5 Resuming Primary Dosing

Press the "Switch to Primary" button at the top of the Manual Mode screen. This now becomes the Primary Console.
Press "Confirm" to start dosing or "Cancel" to cancel.

NOTE:

The NO dose used in Manual Mode will become the set target dose in Primary Mode.

3.6 Adjusting the Dose

To adjust the dose of nitric oxide administered per hospital protocol/physician order. Follow the instructions listed below.

3.6.1 Adjusting the Dose when using a Circuit with an Adaptive Sensor

Press the gray "Set" button to access the electronic keypad on the display screen on the Dosing Console.
Enter the prescribed (ppm) dose using the electronic keypad.
Press "OK" to confirm the dose and to start dosing administration.

3.6.2 Adjusting the Dose when using a Circuit without an Adaptive Sensor

Press the gray "Set" button to access the electronic keypad on the display screen on the Dosing Console.
Enter the prescribed (ppm) dose using the electronic keypad.
Adjust Total Flow Range, if necessary.
Press "OK" to confirm the dose and to start dosing administration.

3.7 Console Use as a Back-Up

This section describes the process of activating the Cassette in the Back-Up Console. Delivery of NO will begin immediately upon Cassette activation.

WARNING: If the dilution flow rate displayed on the screen does not match the ventilator dilution flow, then the estimated NO may be inaccurate.

Press the "Set" button on the Back-Up Console which will display the NO dose numeric keyboard and Flow Section menu.
Confirm Dose and Total Flow range is appropriately selected.
Press "OK" to confirm entry
Connect Adaptive Sensor to the front of the new Dosing Console

NOTE:

The default Total Flow range displayed will be <2.5 LPM unless otherwise selected by the user.
The Back-Up Console is now the Primary Console.
Dosing has been initiated at the default setting of 20 ppm.

4 CONSOLE SHUTDOWN AND CASSETTE DISPOSAL

WARNING: NEVER turn the rear power switch OFF until the System has gone through a controlled shutdown or instructed by VERO Technical Support. Turning the rear power switch OFF prematurely (e.g., while it is still in use) will immediately shut down the device. This may result in interruption in NO delivery to the patient, which may cause injury or death.

CAUTION:

NEVER turn the rear power switch OFF until the System has gone through a controlled shutdown or instructed by VERO Technical Support. Turning the rear power switch OFF prematurely (e.g., while it is still in use) will immediately shut down the device and may cause improper operation upon restart.
ALWAYS power down the GENOSYL DS Console and disconnect the power to the Console when not in use. Failure to do so may lead to permanent damage to the Console.

4.1 Console Shutdown

If the administration of NO must be stopped, then the dose level must be set to "0" and the Cassette must be removed prior to shutting down the Console.

1. Press the gray "Set" button to access the electronic keypad on the display screen.

2. Set the dose to "0" using the electronic keypad.

3. Press "OK" to confirm the entry.

4. If the Settings Tab is not displayed, press the "Menu" tab to access the sub-level tabs.

5. Press the "Settings" tab on the display menu.

6. Press the red "System Shut Down" icon.

7. Press "Confirm" to confirm shutdown.

8. Wait until the Console shuts down, the display screen appears blank, and the Console emits an audible beep.

NOTE: The Console will inert any remain contents from a dosing Cassette upon ejection rendering it unusable. If a Cassette has only been preheated, and not used for dosing, the contents have not been inerted and it can still be used

9. Open the Cassette Access Door.

10. Remove the Cassette by pulling the Cassette straight out.

11. Dispose the Cassette per hospital policy.

12. Press the Black Rocker Power Switch to the "OFF" position.

CAUTION:

NEVER turn the rear power switch OFF until the System has gone through a controlled shutdown or instructed by VERO Technical Support. Turning the rear power switch OFF prematurely (e.g., while it is still in use) may cause improper operation.
ALWAYS power down the GENOSYL DS Console and disconnect the power to the Console when not in use. Failure to do so may lead to permanent damage to the Console.

13. Repeat steps 1-12 for the other Console.

NOTE: If the System does not shut down, see Troubleshooting, Section 8 of the Operator's Manual.

4.2 Cassette Disposal

Following use, any remaining Cassette liquid contents are purged into an inerting chamber that is built into the Cassette, where the contents are chemically neutralized, rendering the Cassette safe for disposal. When the Cassette liquid contents are emptied into the inerting chamber, the Cassette State Window on the front of the Cassette reddens and bleaches from its original blue color, indicating the Cassette is depleted. The Cassette can now be disposed of per hospital policy.

5 ALARMS, ALERTS, AND TROUBLESHOOTING

WARNING: ALWAYS ensure patient safety before troubleshooting (such as an activated alarm) or replacing a problematic item. Not monitoring the patient prior to attending to an alarm can result in injury or death.

5.1 Alarms, Alerts, and Troubleshooting

Section 8.1 of the Operator's Manual contains the system alarms and message in order of High (red), Medium (yellow), and Low Priority (cyan) followed by Informational Messages (green). The table shows the alarm/symptom, the possible cause(s) of the alarm and recommended action to resolve the alarm. If the alarm/issue cannot be resolved, contact Technical Support at 877-337-4118.

A sample screen with an active alarm is shown below:

The alarm banner contains a drop-down menu containing a list of all alarms should there be multiple activated. The alarm icon is always present on the top right of the screen and tapping the icon will pre-silence or silence alarms. Refer the table below for descriptions of each alarm status:

ALARM ICON DISPLAY	DESCRIPTION
	No active alarm condition is detected on the Console. Tap this icon to activate the Pre-Silence feature.
	Alarms are actively pre-silenced. Countdown of time remaining appears under the icon. Pre-silence lasts for 120 seconds. Low/High NO, High NO2, Low/High O2, Water Trap Removed and Dosing Cassette Removed alarms are pre-silenced. Alarms will still be visible on alarm banner but audible alarm will not sound.
	Console has an active alarm condition that requires attention. Tap the icon to silence the alarm for 120 seconds.
	Console has an active alarm condition that requires attention and the alarms have been silenced. Countdown of time remaining appears under the icon.

6 MAINTENANCE

6.1 Calibration

WARNING:

ONLY use the calibration gas pressure regulators supplied by the manufacturer. Pressure regulators not supplied by the manufacturer may damage the sensors and may lead to patient injury.
ALWAYS verify the correct NIST traceable calibration gas is being used and confirm the expiration date of the calibration gas prior to performing calibration. The use of incorrect or expired gas may result in inaccurate sensor readings and can lead to patient injury.
NEVER perform NO or NO2 calibration within the MR scanner room. Calibration equipment is a potential projectile hazard.

CAUTION:

ALWAYS perform a full-scale calibration of the GENOSYL DS when prompted by the System prior to use.
ALWAYS confirm the correct flow direction of the installed one-way check valve in the sampling tee to avoid over pressurization of the sampling system and damage to the device.

6.1.2 Air Calibration

Air Calibration will take up to 2 minutes. A progress bar is displayed in the lower left-hand corner of the display screen during the calibration process.

Check to make sure nothing is connected to the CAL port during Air Calibration.
If the Calibration Tab is not displayed, press the "Menu" tab to access the sub-level tabs.
Press the "Calibration" tab on the display menu.
Press the Low Range "Air" button.
Press the blue "Start Calibration" button.
Press "OK" to continue once calibration is complete.

NOTE: If calibration fails, check if there is anything connected to the CAL port.

6.1.3 NO Calibration

WARNING:

DO NOT open the valve prior to connecting to the CAL port. Opening the valve first will expose the user to NO gas.
DO NOT interrupt calibration until finished. If interrupted, calibration will be cancelled.
DO NOT disconnect tubing from the calibration port prior to closing the valve. Disconnecting the tubing first will expose the user to NO gas.

NOTE: NO calibration takes approximately 2 minutes. A progress bar is displayed in the lower left-hand corner of the display screen during the calibration process.

If the Calibration Tab is not displayed, press the "Menu" tab to access the sub-level tabs.
Press the "Calibration" tab on the display menu.
Press the High Range "NO" button.
Press the blue "Start Calibration" button.
Follow the onscreen instructions.
Press "OK" to continue once calibration is complete.

6.1.4 NO2 Calibration

WARNING:

DO NOT open the valve prior to connecting to the CAL port. Opening the valve first will expose the user to NO2 gas.
DO NOT interrupt calibration until finished. If interrupted, calibration will be cancelled.
DO NOT disconnect tubing from the calibration port prior to closing the valve. Disconnecting the tubing first will expose the user to NO2 gas.

NOTE: NO2 calibration takes approximately 2.5 minutes. A progress bar is displayed in the lower left-hand corner of the display screen during the calibration process.

If the Calibration Tab is not displayed, press the "Menu" tab to access the sub-level tabs.
Press the "Calibration" tab on the display menu.
Press the High Range "NO2" button.
Press the blue "Start Calibration" button.
Follow the onscreen instructions.
Press "OK" once calibration is complete.

6.2 Maintenance Schedule

The Console components require the following maintenance:

COMPONENT	SCHEDULE
Water Trap	Per patient or as required (per Leak Test)
Console	Yearly

The Console requires yearly factory service. The System will display an Information Message to remind the operator when service is required. Call Technical Support at 877-337-4118 to schedule service.

6.3 Water Trap Maintenance

6.3.1 Emptying the Water Trap

WARNING: ALWAYS empty Water Trap before each use, when prompted by the System, and when the trap is more than half full. Allowing the Water Trap to completely fill will occlude the Sample Line which will interrupt patient gas NO, NO2, and O2 concentration monitoring. Failure to monitor the patient gas NO, NO2, and O2 concentrations may result in patient injury.

Remove Water Trap from Console by lifting latch and pulling the base of the Water Trap away from the Console.
Remove the lid by pulling the lid from the base.
Empty the liquid contents.
Clean the Water Trap per hospital policy and cleaning instructions in the Operator's Manual.
Reattach the lid by pushing it back onto base.
Slide the Water Trap back on the Console until it clicks into place.

6.3.2 Water Trap Replacement

WARNING:

ALWAYS use a Water Trap supplied by the manufacturer. Using an incorrect water trap could result in non-functioning or inaccurate sensor readings.
ALWAYS conduct a Water Trap test every time you empty and replace the Water Trap, as failure to do so may lead to an incorrect NO reading, which can result in injury or death.

If the Water Trap / Sample Line Leak Test does not meet requirements and the Sample Line integrity is confirmed or remains occluded, replace the Water Trap.

Remove old Water Trap from Console by lifting the latch and pulling the base of the Water Trap away from the Console.
Slide new Water Trap back on the Console until it clicks into place.
Discard the old Water Trap.

6.4 Battery

The battery will be serviced during scheduled maintenance performed by the manufacturer. If the need arises to replace the battery sooner than scheduled contact Technical Support at 877-337-4118 to schedule a maintenance appointment.

During storage, the GENOSYL DS may be stored with the power off, but the external power supply should be connected at least once every 3 months to ensure a minimum charge is maintained on the internal battery.

WARNING: ONLY properly trained personnel should replace the battery. Incorrectly replacing the battery may result in a hazard such as excessive temperatures, fire, or explosion.

6.5 Cleaning

CAUTION:

ALWAYS power down the GENOSYL DS Console and disconnect the power to the Console when not in use. Failure to do so may lead to permanent damage to the Console.
DO NOT sterilize (e.g., autoclave, gas sterilize) any of the components of the System, as this may compromise performance.
DO NOT use harsh cleaning agents on the GENOSYL DS. Doing so may impair the structural integrity and/or function of the device.
ONLY use a damp cloth to clean the Console and limit use of liquids around Console. Excess water can permanently damage the device.
ALWAYS ensure the System is completely dry after cleaning before powering it ON. Failure to do so could result in equipment damage.

6.5.1 Enclosure, Connections, and Surfaces Other Than the Display

Prior to performing any cleaning or maintenance operations ensure that the GENOSYL DS Console has been completely powered down and that the AC/DC power supply external to the GENOSYL DS Console has been unplugged. Apply any mild detergent to cloth prior to wiping down the System. Gently clean the outer surface of the unit with a soft damp cloth and mild detergent or isopropyl alcohol (70%).

WARNING:

NEVER submerge the GENOSYL DS, Cassette, or non-disposable Adaptive Sensor Cable. Submerging in liquid will damage the System and could cause electrical shorts which may result in injury or death.
DO NOT clean the GENOSYL DS with the power connected and the System turned ON, as this may lead to injury (e.g., shock). Unplug AC/DC power supply external to the System prior to cleaning.

6.5.2 Display Screen

Turn off Console and disconnect from AC power. Gently clean with a damp cloth.

CAUTION:

DO NOT touch or rub the display screen with abrasive cleaning compounds or organic solvents, as they may scratch and damage the screen.
DO NOT spray or pour liquids directly on the controller or the display, as they may damage the screen.

6.6 Storage

6.6.1 Cart / Console Storage

The acceptable storage conditions for the cart/Console are shown in the following table.

Cart / Console Storage	Temperature	-20°C to 60°C
	Humidity	15% to 95%, non-condensing
	Pressure	57kPa to 110kPa

During storage, the GENOSYL DS may be stored with the power off, but with the external power supply connected in which case the internal battery will be kept fully charged.

WARNING:

MAKE SURE the GENOSYL DS is connected to AC wall power to charge the battery a minimum of once every 3 months to maintain a minimum battery charge. Failure to recharge the Console battery for extended timeframes may result in full discharge of the battery. If a Battery Error message occurs during startup of the System, contact Technical Support at 877-337-4118 for assistance.
ONLY properly trained personnel should replace the battery. Incorrectly replacing the battery may result in a hazard such as excessive temperatures, fire, or explosion.
ONLY store the GENOSYL DS as outlined in the storage instructions. Not storing the device in alignment with its storage instructions can cause the device to be unsafe and lead to injury or death.

6.6.2 Cassette / Accessory Storage

The GENOSYL DS may not function correctly if the Cassette or any of the System Accessories have been exposed to high levels of heat or humidity. Cassettes are supplied in a plastic container and should remain unopened until use. Cassettes should be stored at 25°C (77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F). (See USP Controlled Room Temperature)

6.7 Ventilator Compatibility

The GENOSYL DS is compatible with the following equipment and accessories:

Table 3: Compatible Equipment and Accessories
MANUFACTURER	TYPE OF EQUIPMENT	MODEL
Fisher Paykel	Vent circuit kit	RT265
Fisher Paykel	Vent circuit kit	RT210
Fisher Paykel	Humidifier	850
Fisher Paykel	Humidifier Chamber	MR 290
Medline	Hyperinflated Resuscitator	Resus Hyperinf System 1/2L-LF
Laerdal	Self-inflated Resuscitator	Infant Silicone Resuscitators

Vero Biotech performs validation testing which determines the compatibility of ventilator/gas delivery systems with the GENOSYL DS. During this compatibility testing, the GENOSYL DS is evaluated for the following parameters while connected to each ventilator/gas delivery system:

NO Dose Accuracy: Continuous and accurate delivery of a targeted dose of nitric oxide within ± 20% of setpoint or within +/- 2 ppm, whichever is greater.
Respiratory Device Gas Delivery and Alarms: The respiratory device gas delivery device and alarms continue to function as intended by the manufacturer across the range of operating conditions.
NO2 Performance: NO2 remains within acceptable limits less than 1.0 ppm with 60% FiO2 and ≤40 ppm NO.
O2 Dilution: Post dilution O2 level delivery is maintained within acceptable limits and conforms with the information presented in the GENOSYL DS Operator's Manual, Section 10.1.1, "Oxygen Dilution".
NO Concentration Transients: NO concentration transients are ≤150% of mean concentration and as low as 0.0 ppm as long as the transient duration does not exceed 10% of the volumetric duration of the breath.

The testing performed demonstrated conformance with all specified requirements.

WARNING:

ALWAYS use the GENOSYL DS in accordance with the indications, usage, contraindications, warnings, and precautions described in the GENOSYL prescribing information and labeling. Refer to latest approved prescribing information and labeling prior to use.
The approved patient population for the GENOSYL DS as specified in the drug labeling for GENOSYL (nitric oxide) for inhalation, is limited to neonates. The GENOSYL DS is not intended to be used in other patient populations.

The following ventilators and non-invasive gas delivery systems have been validated for use with the GENOSYL DS. See Section 1 for assembly instructions for Injection Assembly with Adaptive Sensor and Mixer Assembly with Adaptive Sensor.

Table 4: Details of Validated Systems
Manufacturer	Model	Neonatal	Pediatric/Adult	CPAP	HFNC	MR
Bio-Med Devices	Crossvent 2+/2i+
Bio-Med Devices	MVP-10
Dräger	VN500
Dräger	V500
GE Healthcare	R860
Hamilton	C1/T1
Hamilton	C2/C3
Hamilton	MR1
Hamilton	G5
Maquet	Servo-U/N/I
Maquet	Servo-I MR
Puritan Bennett	840
Puritan Bennett	980
Vyaire Medical Inc.	AVEA
Fisher & Paykel	Optiflow Jr Breathing Circuit
Fisher and Paykel	Optiflow Breathing Circuit
Fisher & Paykel	Bubble CPAP System

Table 5: Validated Compatibility with and without Inline Mixer

See Section 1 for assembly instructions for Injection Assembly with Adaptive Sensor and Mixer Assembly with Adaptive Sensor.

Manufacturer	Model	Ventilator Range Tested: Neonatal	Ventilator Range Tested: Pediatric/Adult
		Ventilator Circuit using Injection Assembly with Adaptive Sensor	Ventilator Circuit using Injection Assembly with Adaptive Sensor	Ventilator Circuit using Mixer Assembly with Adaptive Sensor
		(Without Inline Mixer )	(Without Inline Mixer)	(With Inline Mixer)
Key: -Range Fully tested; use of Inline Mixer is not recommended VT – Tidal Volume VT Value listed – Tidal volumes in this range have been validated in accordance with column header
Bio-Med Devices	Crossvent 2+/2i+			N/A
Bio-Med Devices	MVP-10			N/A
Dräger	VN500			N/A
Dräger	V500		VT < 400ml	VT > 400 – 600ml
GE Healthcare	R860		VT < 350ml	VT > 350 – 650ml
Hamilton	C1/T1		VT ≤ 450ml	VT > 450 – 600ml
Hamilton	C2/C3		VT ≤ 470ml	VT > 470 – 950ml
Hamilton	MR1		VT ≤ 470ml	VT > 470 – 950ml
Hamilton	G5		VT ≤ 950ml	VT > 950 – 1400ml
Maquet	Servo-U/N/I		VT ≤ 650ml	VT > 650 – 740ml
Maquet	Servo-I MR		VT ≤ 650ml	VT > 650 – 740ml
Puritan Bennett	840		VT < 300 mL	VT > 300-760 mL
Puritan Bennett	980		VT ≤ 485ml	VT > 485 – 1100ml
Vyaire Medical Inc.	AVEA		VT < 540ml	VT ≥ 540ml

VERO Biotech and GENOSYL are registered trademarks of Vero Biotech Inc.
© 2023 VERO Biotech. Printed in U.S.A. LBL-602503 Rev D JAN 2023
Please read full prescribing information enclosed.
877.337.4118 | vero-biotech.com

PRINCIPAL DISPLAY PANEL - 216 L Cartridge Label

GENOSYL® (nitric oxide) for inhalation

Recommended Dosage: See prescribing information.

For use with GENOSYL Delivery System only

LOT Z-XXXX-YYYY

SN ZZXXZXXX

EXP YYYY-MM-DD

Patents: http://www.vero-biotech.come/patents

Rx Only

800 PPM

NDC: 72385-002-01

Bar Code

7238500201

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Manufactured by VERO Biotech Inc.

VĒRO
BIOTECH

602085-01 Rev K

PRINCIPAL DISPLAY PANEL - 216 L Cartridge Label

INGREDIENTS AND APPEARANCE

GENOSYL
nitric oxide gas

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 72385-002
Route of Administration	RESPIRATORY (INHALATION)

Ingredient Name	Basis of Strength	Strength
Active Ingredient/Active Moiety
NITRIC OXIDE (UNII: 31C4KY9ESH) (NITRIC OXIDE - UNII:31C4KY9ESH)	NITRIC OXIDE	0.98 mg in 1 L

#	Item Code	Package Description	Marketing Start Date	Marketing End Date
Packaging
1	NDC: 72385-002-01	216 L in 1 CARTRIDGE; Type 0: Not a Combination Product	12/28/2022

Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Marketing Information
NDA	NDA202860	12/28/2022

Labeler - VERO BIOTECH, INC. (872672477)

Registrant - VERO BIOTECH, INC. (872672477)

Name	Address	ID/FEI	Business Operations
Establishment
VERO BIOTECH, INC.		872672477	manufacture(72385-002)

Trademark Results [GENOSYL]

Mark Image Registration \| Serial	Company Trademark Application Date
GENOSYL 87772550 not registered Live/Pending	VERO BIOTECH, LLC 2018-01-26
GENOSYL 85981080 4496333 Live/Registered	GeNO LLC 2011-12-02
GENOSYL 85485604 4700107 Live/Registered	VERO BIOTECH, LLC 2011-12-02

Room size	1000 ft3
Room volume	28,300 L
Room ventilation (6 complete exchanges/hour)	2,830 L/min
NO flow into the room	80 ppm at 14 L/min
Average NO room concentration (80 × 14) ÷ 2,830 = 0.396 ppm (0.4 ppm)	0.4 ppm of NO

Alarm Priority	Color	Flashing Frequency	Flashing Duty Cycle	Sound Level
High	Red	1.4 to 2.8 Hz	40-60%	79.8 dBA
Medium	Yellow	0.4 to 0.8 Hz	40-60%	76.1 dBA
Low	Cyan	Constant (on)	100%	63.3 dBA

Alarm	Adjustment Range	Default Setting	Alarm Activation	Interruption Condition
High NO (ppm)	0 – 100 ppm	+ 50% of set value or 2 ppm (Whichever is greater)	10 minutes after dose >0 ppm entered	≥ 100 ppm
Low NO (ppm)	0 – 99 ppm	- 50% of set point or 2 ppm (Whichever is greater)	10 minutes after dose >0 ppm entered	NA
High NO2 (ppm)	1-2.9 ppm	3 ppm	30 seconds after dose > 0 ppm entered	≥ 3 ppm
High O2 (% v/v)	22 – 100 ppm	100 ppm	Immediately after dose > 0 ppm entered	N/A
Low O2 (% v/v)	18 – 99 ppm	18 ppm	Immediately after dose > 0 PPM entered	N/A

High Priority Alarms and Messages
Alarm/Symptom	Possible Cause	Recommended Action
Nitric Oxide Delivery Interruption due to Flow Not Detected Message Box:	Adaptive Sensor not detecting flow Cause not determined	Once flow is detected through the Adaptive Sensor, dosing will resume automatically and this fallback mode will be cancelled. 1. Verify proper connection of Adaptive Sensor to respiratory circuit 2. Verify flow is present in the respiratory circuit
Banner:	Adaptive Sensor not detecting flow Cause not determined
Nitric Oxide Delivery Interruption due to High NO Message Box:	Flow changed abruptly in respiratory circuit Low or no flow in patient respiratory circuit Cause not determined	This fallback mode will be cancelled once the nitric oxide level drops below the set dose + 20%. 1. Verify flow is present in the patient's respiratory circuit. 2. Allow time for the sensor measurement to adjust while completing the next steps. 3. Verify GENOSYL DS gas line connections are tight by loosening then retightening each connection on the red injection and blue sample lines. 4. If the sensor measurement does not adjust, switch to Back-up Console. 5. Call Technical Support.
Banner:
Screen Display:
Nitric Oxide Delivery Interruption due to High NO2
Message Box:	Low or no flow in patient respiratory circuit Respiratory flow changed abruptly Leak in patient respiratory circuit Cause not determined	This fallback mode will be cancelled once the NO2 level drops below 3 ppm. 1. Ensure flow from patient's respiratory device. 2. Allow time for the sensor measurement to adjust while completing the next steps. 3. Verify GENOSYL DS gas line connections are tight by loosening then retightening each connection on the red injection and blue sample lines. 4. If the sensor measurement does not adjust, switch to Back-up Console. 5. Call Technical Support.
Banner:
Screen Display:
High NO Alarm Message Box: None	Respiratory circuit flow changed abruptly Low or no flow in patient respiratory circuit High NO alarm may be inappropriately set Cause not determined	1. Verify flow is present in the patient's respiratory circuit. 2. Allow time for the sensor measurement to adjust while completing the next steps. 3. Verify GENOSYL DS gas line connections are tight by loosening then retightening each connection on the red injection and blue sample lines. 4. Go to the Alarms screen and check the NO alarm setting. Set alarm to the desired setting. 5. If the sensor measurement does not adjust, switch to Back-up Console. 6. Call Technical Support.
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High NO2 Alarm Message Box: None	Low or no flow in patient respiratory circuit Ventilator flow changed abruptly High NO2 alarm may be inappropriately set Cause not determined	1. Verify flow is present in the patient's respiratory circuit. 2. Allow time for the sensor measurement to adjust while completing the next steps. 3. Verify GENOSYL DS gas line connections are tight by loosening then retightening each connection on the red injection and blue sample lines. 4. Go to the Alarms screen and check the NO2 alarm setting. Set alarm to the desired setting. 5. If the sensor measurement does not adjust, switch to Back-up Console 6. Call Technical Support
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Low NO alarm Message Box: None	Gas lines are not connected or properly placed in the respiratory circuit Water Trap full Leak in respiratory circuit Alarm limit not adjusted properly NO Cassette needs to be replaced Cassette is depleted without a second Cassette inserted Gas sample tee placed too close to patient wye adapter Cause not determined	1. Verify GENOSYL DS gas line connections are tight by loosening then retightening each connection on the red injection and blue sample lines. 2. Ensure gas sample tee is placed 6 to 12 inches from the patient wye adapter. 3. Check the respiratory circuit for the presence of leaks. 4. If not using an Adaptive Sensor, confirm total flow range is properly selected. 5. Allow time for the sensor measurement to adjust while completing the next steps. 6. Empty Water Trap. Replace Water Trap if necessary. 7. If Cassette is depleted, insert a second Cassette if not already present. If auto transition does not occur, switch to Back-up. 8. Ensure dose and flow are set within specifications. (see Section 10.1.4 Liters per minute multiplied by ppm should not exceed 800. (Example 40 LPM x 20ppm = 800) 9. Go to alarms screen and check the NO alarm setting. Set the alarm to the desired setting. 10. If sensor measurement does not adjust, switch over to Back-up Console. 11. Call Technical Support.
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Calibration Required Message Box: None	Calibration for the sensor is required	This fallback mode will be cancelled once a successful high gas calibration has been completed. 1. Calibrate Console (see Section 9.1). 2. If the calibration required alarm occurs after a successful calibration has been completed, call Technical Support.
Banner:	Calibration for the sensor is required
Hardware Failure Message Box:	Internal hardware damage or communication failure	In this fallback mode, the Console will continue delivering nitric oxide in an open loop mode at the last entered dose. 1. Switch to Back-up Console. 2. Call Technical Support.
Banner:	Internal hardware damage or communication failure
Hardware Failure – Power Board Message Box:	Internal hardware damage or communication failure	1. Switch to Back-up Console. 2. Call Technical Support.
Banner:	Internal hardware damage or communication failure	1. Switch to Back-up Console. 2. Call Technical Support.
Hardware Error During POST (Power On Self-Test) Message Box:	Problem occurring during boot-up sequence Internal hardware damage or communication failure	1. Use other Console if NO delivery is needed immediately. 2. Re-boot by holding Silver Power Button down for 10 seconds. 3. If error message continues, call Technical Support.
Battery Error Message Box: None	Internal battery error or battery fails to charge Battery becomes disconnected	1. Plug in AC power. 2. Verify power connections on Console, power adapters, and AC power source. 3. If error persists and not dosing, re-start Console. 4. If alarm does not clear, switch to Back-up Console and call Technical Support
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Line Occlusion (Sample) Message Box: None	Stopcock valve on the Sample Line (blue) is in the closed position Water Trap is full Blue Sample Line is kinked or occluded Cause not determined	In this fallback mode, the Console will continue delivering nitric oxide in an open loop mode at the last commanded dose until the line occlusion is resolved. 1. Ensure blue Sample Line Stopcock is in the open position. 2. Empty Water Tap. 3. If occlusion persists after emptying, replace Water Trap. 4. Inspect entire length of blue sample line for kinks or occlusions. 5. Replace gas lines if kink or occlusion cannot be resolved. 6. If issue is still not resolved, switch over to Back-up Console. 7. Call Technical Support.
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Line Occlusion (Cal) Message Box: None	Potential obstruction to calibration port Calibration tank valve closed during high calibration procedure Cause not determined	1. Ensure calibration port is free of debris or damage and nothing is connected. 2. Perform high calibration by following procedure in Section 9.1 3. If issue is still not resolved, switch over to Back-up Console. 4. Call Technical Support
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Cassette Removed while dosing Message Box:	Cassette manually ejected using emergency ejection tabs Hardware damage which causes the System to not be able to detect the Cassette Cause not determined	1. If secondary Cassette is not inserted, transition to Back-up Console 2. Call Technical Support.
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Water Trap Not Detected Message Box:	Water Trap not seated properly Water Trap not present Cause not determined	In this fallback mode, the console will continue delivering nitric oxide in an open loop mode at the last commanded dose until the water trap is replaced and the leak check is passed. 1. Re-seat Water Trap. 2. Insert new Water Trap. 3. Switch over to Back-up Console. 4. Call Technical Support.
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Configuration Parameters Incorrect Message Box:	File integrity issue	1. Use other Console if NO delivery is needed immediately. 2. Call Technical Support.
Battery Not Detected during POST (Power On Self- Test) Message Box:	Battery is not connected properly or not operational	1. Use other Console if NO delivery is needed immediately. 2. Call Technical Support.
Hardware Error During POST (Power On Self-Test) Message Box:	Hardware failure occurred	1. Use other Console if NO delivery is needed immediately. 2. Call Technical Support.
Banner:	Hardware failure occurred
Cassette Not Operational Message Box:	Hardware failure within Cassette during dosing	If a secondary Cassette is inserted in the other slot, the Console will automatically switch to the secondary Cassette in this fallback mode. 1. If a secondary Cassette is not inserted in the other slot, switch to Back-up Console. 2. Replace Cassette in original Dosing Console 3. If issue is not resolved, switch to Back-up Console. 4. Call Technical Support.

Medium Priority Alarms and Messages
Alarm/Message	Possible Cause	Recommended Action
Low Battery Alarm Message box: None Banner:	Battery is low	1. Verify power connections on console, power adapters, and AC power source. 2. If AC power is not available, switch to Back- up Console. 3. Then plug into AC power as soon as possible.
Cassette Failure Alarm	Internal Cassette issue	1. Replace with a new Cassette. 2. If unresolved, switch to Back-up Console and call Technical Support.
Service Due Date Expired	Scheduled yearly Service date is past due	1. Accept message. 2. Call Technical Support to service System.
Cassette to Expire in 1 Hour	Cassette will deplete in 1 hour	1. Ensure secondary Cassette is inserted and ready. 2. Replace Cassette once transition is complete.
Low O2 Message box: none Banner:	Respiratory device setting is incorrect Alarm setting is incorrect Ventilator flow is too low	1. Verify respiratory device setting is correct. 2. Set the alarm ranges to the correct setting. 3. Calibrate Console (see Section 9.1). 4. If sensor measurement does not adjust, switch over to Back-up Console. 5. Call Technical Support.
High O2 Message Box: none Banner:	Respiratory device setting is incorrect Alarm setting is incorrect	1. Verify respiratory device setting is correct. 2. Set the alarm ranges to the correct setting. 3. Calibrate Console (see Section 9.1). 4. If sensor measurement does not adjust, switch over to Back-up Console. 5. Call Technical Support.
Delivery Flow Error Message Box:	Red injection line is kinked or occluded Kink or occlusion in respiratory circuit NO port is occluded Hardware issue caused a failure	1. Inspect entire length of red injection line for kinks and occlusions. 2. Insect respiratory circuit for kinks or occlusions 3. Inspect NO output port on front of console for debris or damage. 4. Ensure the air intake is not blocked. 5. Resolve the kink or blockage. 6. If problem persists, call Technical Support.
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NO	time-weighted (8 hours) average concentration limit of 25 ppm
NO2	Recommended exposure limit of 1 ppm

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. If actively dosing, switch to Manual prior to completing the following steps (see Section 5.4 for details on Manual Mode).	WARNING
		Failure to switch to Manual Mode prior to installing a Sample Line Extension when the System is actively dosing may result in a spike in the NO dose delivered to the patient.
	2. Turn the blue Stopcock Valve, attached at the Gas Sample Tee, to the closed position as shown.
	3. Push and twist counterclockwise the Luer-Lock Collar of the Sample Line to remove from the blue Stopcock Valve at the Gas Sample Tee.
	4. Push and twist clockwise the Luer-Lock Collar of the Sample Line onto the Sample Line Extension female connection. 5. Push and twist clockwise the Luer-Lock Collar of the Sample Line onto the blue Stopcock Valve at the Gas Sample Tee.
	6. Perform Water Trap/Sample Line Leak Test, as detailed in Section 2.13.
	7. If actively dosing, switch back to Primary mode (see Section 5.4.2 for details on resuming Primary dosing).

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	Push and twist clockwise the Luer-Lock Collar from the NO Injection Line onto the Injection Assembly.	NOTE
		After connecting, the valve assembly may have rotated such that the orientation may appear different from what is shown here and on the display screen.
	2. Push and twist clockwise the Luer-Lock Collar of the Sample Line onto the Sampling Port of the Gas Sample Tee.	NOTE
		Skip this step if a Gas Sample Tee is already connected and in-line with the ventilator circuit.
	3. Ensure the blue Stopcock Valve is in the open position as shown.
	4. Connect the distal end of the Adaptive Sensor Cable to the Adaptive Sensor on the Injection Assembly

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Disconnect the Inspiratory Tubing from the humidifier and attach it to the proximal end of the Injection Assembly to the Adaptive Sensor. 2. Attach the distal end of the Injection Assembly to the humidifier.
	3. Insert the Sample Tee into the ventilator circuit at the proximal end of the temperature probe closest to the patient.	NOTE
		If a Gas Sample Tee is already connected and in-line with the ventilator circuit, connect the blue Sample Line directly to the existing Gas Sample Tee.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Push the Circular Power Connectors into the back of the top and bottom Consoles. 2. Connect the main power cord to a grounded 120 V electrical outlet.	CAUTION
		ONLY use the GENOSYL DS with the power cord supplied by the manufacturer. Use of a generic power cord may cause output voltage instability leading to a touch screen failure. ALWAYS ensure the power cord is firmly seated into the power supply and the wall outlet. A loose connection can result in damage to the device or faulty operation.
	3. Press the Black Rocker Power Switch, located on the back of each Console, to the right (ON position) to power on both Consoles.
	4. Press the Silver Power Button, located at the top left corner on the front panel of each Console, to turn on the display screens on both Consoles. The display screen will illuminate, and the Consoles will beep, indicating the power is on.	CAUTION
		The System will conduct an internal self-test. If an alarm or failure message should occur, refer to Section 8 to resolve the issue.
		NOTE
		If the display screen does not turn on, see Troubleshooting, Section 8.7.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	The following steps should be taken to insert the Cassettes into the Consoles.	WARNING
		ALWAYS follow Cassette inspection instructions prior to Cassette insertion. Not inspecting the Cassette prior to insertion may lead to using a faulty Cassette, resulting in injury.
		NOTE
		Upon turning on the Consoles, the Cassette Indicator will display "Replace"
	1. Confirm the Cassette State Window on each Cassette is blue.	WARNING
		DO NOT use the Cassette if the window is not blue. A Cassette State Window that is any color other than blue may affect the Cassette's ability to provide the correct NO dosage to the patient, which may cause injury or death.
		NOTE
		Cassette is inserted front first. The Cassette State Window is not visible when properly inserted. If the Cassette State Window is not blue, see Troubleshooting, Section 8.7.
	2. Open the Cassette Access Doors and insert two Cassettes into the Dosing Console and at least one Cassette into the Back-up Console. Push until it clicks.	NOTE
		Make sure Consoles are turned on before inserting the Cassette. The Water Trap / Sample Line Leak Test is automatically initiated when the Cassette has been inserted and the measured NO is less than 1.0 ppm. After the first Cassette is fully inserted, the Operator will have 60 seconds to close the blue Stopcock Valve to perform the test (Step 3 below). Gas lines will need to be connected to the Console in order to pass the Water Trap/ Sample Line Leak Test.
		NOTE
		The Display Screen will temporarily indicate the Cassette has been detected, then automatically transition to the Water Trap / Sample Line Leak Test screen.
	3. Follow the onscreen instructions on both Consoles.	NOTE
	3. Follow the onscreen instructions on both Consoles.	The screen will indicate the Water Trap / Sample Line Leak Test has started and the progress bar will be red until the stopcock valve has been closed, upon which it will then turn green if there is no leak detected. Pressing "Cancel Leak Test", will allow for dosing in Manual Mode. See Section 5.4 for detail around dosing in Manual Mode.
	4. Follow the onscreen instructions on both Consoles.	CAUTION
	4. Follow the onscreen instructions on both Consoles.	Open the blue Stopcock Valve prior to pressing "Accept". Failure to do so will result in a line occlusion alarm.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. If this screen is displayed, follow the onscreen instructions on both Consoles.
	2. Press Confirm on both Consoles to begin a new Water Trap / Sample Line Leak Test.	NOTE
		NO Injection is held at 20 ppm until the completion of a successful Water Trap / Sample Line Leak Test.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Press the gray "Set" button on the display screen.
	2. Confirm Total Flow Range is appropriately selected. 3. Enter the prescribed dose in ppm on the electronic keypad. 4. Press OK to confirm the entry.	NOTE
		The time to reach target dose may vary up to 10 minutes. If unable to set the dose in Primary Mode, see Troubleshooting, Section 8.7.
		NOTE
		If manual ventilation is required, proceed to Section 5.4. When adjusting dose, proceed to Section 5.2. If dosing is completed, proceed to Section 6.1.
		NOTE
		The display screen will look as shown after completing steps 1-3.
		NOTE
		The NO2 sensor reading may appear as "--" for the first 30 seconds of dosing while the sample system is preparing.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Press the gray "Set" button to access the electronic keypad on the display screen on the Dosing Console.
	2. Enter the prescribed dose using the electronic keypad. 3. Press "OK" to confirm the dose and to start dosing administration.	NOTE
		If dosing is complete, proceed to Section 6.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Press the gray "Set" button to access the electronic keypad on the display screen on the Dosing Console.
	2. Enter the prescribed ppm dose using the numeric keypad. 3. Adjust Total Flow Range, if necessary. 4. Press "OK" to confirm the dose and to start dosing administration.	NOTE
		If dosing is complete, proceed to Section 6.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
		NOTE
		The Console will automatically transition to the secondary Cassette if properly inserted and preheated. The screen to the left will be displayed during the transition process.
	1. Follow onscreen instructions to replace Cassette.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Ensure the oxygen flow source is set appropriately or adjust as needed. 2. Press the button "Switch to Manual" on the Dosing Console.
	3. Press Confirm to switch to Manual Dosing.	WARNING
	3. Press Confirm to switch to Manual Dosing.	If the dilution flow rate displayed on the screen does not match the wall source, then the estimated NO may be inaccurate.
		NOTE
		Dosing has been initiated at the same dose setting (ppm) as in Primary Mode. If the primary dosing was set at "0" prior to pressing the "Switch to Manual" button, the estimated NO will also be at "0" and will need to be adjusted. If the dose was set between 1 and 5 ppm prior to pressing the "Switch to Manual" button, the estimated NO dose will also be at "5 ppm" and may be adjusted.
	4. To resume primary dosing, see Section 5.4.3.	NOTE
	4. To resume primary dosing, see Section 5.4.3.	If an adjustment of the NO concentration is required, press the green up and down arrows. If an adjustment to the Dilution Flow Rate is required while in Manual Mode, press the LPM value and a drop-down menu will expand. Press the prescribed value. The new value will be highlighted in blue and the drop-down menu will collapse.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Navigate to the Settings Tab.
	2. Select the Flow Rate from the drop-down menu.	NOTE
	2. Select the Flow Rate from the drop-down menu.	The Console will default to a Flow Rate of 10 LPM if not adjusted. Any adjustment will be retained until the Console is powered down.

ILLUSTRATION	ACTION	Warnings, Cautions and Notes
	1. Press the "Switch to Primary" button at the top of the Manual Mode screen.
	2. Press "Confirm" to start dosing or "Cancel" to cancel.	NOTE
	2. Press "Confirm" to start dosing or "Cancel" to cancel.	The NO dose used in Manual Mode will become the set target dose in Primary Mode.
		NOTE
		The display screen will look as shown after completing steps 1-2.

DISPLAY	ACTION	Warnings, Cautions and Notes
	1. Press the "Set" button on the Back-up Console which will display the NO dose electronic keypad and Flow Selection menu.
	2. Confirm Dose and Total Flow range is appropriately selected. 3. Press "OK" to confirm entry	NOTE
		The Back-up Console screen will be as shown. The default Total Flow range displayed will be <2.5LPM and the default dose will be 20 ppm unless otherwise selected by the user. See Section 5.1.2 The Back-up Console is now the Dosing Console.
	4 Connect the Adaptive Sensor Cable to the front of the new Dosing Console.

Low Priority Messages and Alarms
Message/Alarm	Possible Cause	Recommended Action
System Running on Battery Only	AC power is not connected	1. Check the AC power connection. 2. Verify power connections on Console, power adapters, and AC power source. 3. If connecting to AC power does not resolve issue, switch to Back-up Console and call Technical Support.
Service Due Date Within 2 Days	Service date is scheduled within 2 days	1. Accept message. 2. Contact Technical Support to have System serviced at earliest convenience.

Issue/Symptom	Possible Cause	Recommend Action
Screen does not turn on	Battery discharged and not connected to AC power Screen malfunction	1. Ensure power is properly connected in the back of the unit and the wall outlet. Green light on power supply should be on. 2. Ensure battery is connected properly. 3. Wait for System to charge. 4. Power on System. 5. If not resolved, switch to Back-up Console and call Technical Support.
Cassette does not insert properly within Console	Drop or other physical damage	1. Discard damaged NO Cassette and replace with new Cassette. 2. If new Cassette does not insert properly, switch to Back-up Console and call Technical Support.
Cassette State Window is not blue	Drop or other physical damage Cassette was previously activated	1. Discard damaged Cassette and replace with new Cassette.
Pumps are louder than normal	Enclosure damage Pump malfunction	1. Call Technical Support.
Cannot set dose in Primary Mode	Flow not detected through Adaptive Sensor Water Trap/ Sample Line Leak Test was not performed Calibration is required for at least one sensor	1. Verify flow is present in patient circuit. 2. Perform Water Trap/ Sample Line Leak Test if not already performed. 3. Perform calibration if required. 4. If issue is not resolved, call Technical Support.
Console does not shutdown	Operating System issue or file corruption	1. Hold the Silver power button on the front down for approximately 10 seconds. The Console should shutdown. 2. If the above does not work, power the Console off with the switch on the back. 3. Contact Technical Support if the issue remains.
Audible alarm tone does not sound after boot-up process	Speaker hardware failure	1. Contact Technical Support.
Failed Water Trap / Sample Line Leak Test	Incorrectly connected the Sample Line to the CAL Port Test timed out at 60 seconds Sample line valve not closed properly Loose gas lines connections Water Trap not sealed completely Water Trap seal leak	1. Ensure proper line connections. 2. Conduct test within 60 seconds. 3. Move the blue stopcock to the closed position. 4. Check Water Trap seal. 5. Replace Water Trap. 6. If issue is not resolved, call Technical Support
Cassette does not automatically eject from Console	Mechanism malfunction	1. Open Cassette Access Door. Simultaneously push the tabs above and below the Cassette to manually eject the Cassette.
Screen Unresponsive	Screen is frozen	1. Switch to Back-up Console. 2. Hold Silver Power Button for 10 seconds. 3. Wait for Console to shut down. 4. Switch off and on black rocker switch. 5. Reboot Console.
Adaptive Sensor Not Detected	Adaptive Sensor Cable Not Connected Adaptive Sensor not Connected to Adaptive Sensor Cable	1. Verify Adaptive Sensor Cable is properly plugged into front of Console and the cable is fully inserted. 2. Detach the Adaptive Sensor from the Adaptive Sensor Cable. 3. Wait at least five seconds. 4. Reattach the Adaptive Sensor to the Adaptive Sensor Cable.
Flow Not Detected	Respiratory Device not delivering flow into circuit Adaptive Sensor not present in circuit	1. Ensure Respiratory Device is delivering flow into circuit. 2. Verify Adaptive Sensor is connected in the circuit.
Adaptive Sensor Icon is Yellow	Adaptive Sensor is not properly connected or has become disconnected Adaptive Sensor is malfunctioning	1. Detach the Adaptive Sensor from the Adaptive Sensor Cable. 2. Unplug the Adaptive Sensor Cable from the Console. 3. Wait at least five seconds and reinsert the Adaptive Sensor Cable into the Console. 4. Reattach the Adaptive Sensor to the Adaptive Sensor Cable. 5. If problem persists, replace the Adaptive Sensor. 6. If problem still persists, call Technical Support.

DISPLAY	ACTION	Warnings, Cautions and Notes
	1. Check to make sure nothing is connected to the CAL port during Air Calibration. 2. If the Calibration Tab is not displayed, press the "Menu" tab to access the sub-level tabs. 3. Press the "Calibration" tab on the display menu. 4. Press the Low Range "Air" button. 5. Press the blue "Start Calibration" button.	NOTE
		Air Calibration will take up to 2 minutes if not dosing, or 5 minutes if actively dosing. A progress bar is displayed in the lower left-hand corner of the display screen during the calibration process.
	6. Press "OK" to continue once calibration is complete.	NOTE
	6. Press "OK" to continue once calibration is complete.	If air calibration fails, ensure that nothing is connected to or blocking the CAL port.

DISPLAY	ACTION	Warnings, Cautions and Notes
	1. If the Calibration Tab is not displayed, press the "Menu" tab to access the sub-level tabs. 2. Press the "Calibration" tab on the display menu. 3. Press the High Range "NO" button. 4. Press the gray "Start Calibration" button.
	5. Follow the onscreen instructions.	WARNING
		DO NOT open the valve prior to connecting to the CAL port. Opening the valve first will expose the user to NO gas. DO NOT interrupt calibration until finished. If interrupted, the calibration will be cancelled.
		NOTE
		NO calibration takes approximately 2 minutes if not dosing, or 5 minutes if actively dosing. A progress bar is displayed in the lower left-hand corner of the display screen during the calibration process.
	6. Follow the onscreen instructions 7. Press "Accept" to continue once calibration is complete.	WARNING
		DO NOT disconnect tubing from the calibration port prior to closing the valve. Disconnecting the tubing first will expose the user to NO gas.

COMPONENT	SCHEDULE
Water Trap	Per patient or as required (per Water Trap/ Sample Line Leak Test)
GaussAlert™	Monthly functionality check
Console	Yearly