a) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta 2 adrenergic agonists and systemic steroid, if bronchospasm develops.
b) DERMAL: Remove contaminated clothes and wash exposed area extremely thoroughly with soap and water. Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
c) OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation or photophobia persist, the patient should be seen in a healthcare facility.

a) Administration of NO can cause severe systemic hypotension in newborns with persistent pulmonary hypertension associated with severe left ventricular dysfunction. This is thought to be due to one of two mechanisms: Nitric oxide's reversal of the right-to-left shunt through the patent ductus arteriosus, or, a massive vasodilation induced by inhaled NO resulting in further left ventricular failure (Henrichsen et al, 1996; Beghetti et al, 1997).
b) CASE REPORT: A decrease in mean systemic arterial pressure (41 to 35 mmHg) was reported in an infant with persistent pulmonary hypertension of the newborn during administration of 7 ppm inhaled nitric oxide (Oriot et al, 1993). The infant also had a paradoxical worsening of hypoxemia in response to nitric oxide, which was attributed to treatment of the mother with indomethacin. The role of nitric oxide alone in producing hypotension in this case is unclear.

a) Endogenous nitric oxide appears to mediate hypotension in septic shock (ACGIH, 1997) (Cobb & Danner, 1996). Hypotension may be a manifestation of the effect of both nitrite and nitrate ions on vascular smooth muscle. Acute overdoses may be expected to produce some degree of hypotension. Measurable vasodilation in extrapulmonary circulation may occur and may be due to binding of NO to circulating albumin or hemoglobin, which are biologically active, and can produce systemic arterial and venous, as well as coronary artery vasodilation (Weinberger et al, 2001).

a) Due to the rapid inactivation of nitric oxide by hemoglobin, therapeutically inhaled nitric oxide has not been associated with significant systemic hemodynamic effects (Rich et al, 1993; Frostell et al, 1993; Kinsella & Abman, 1993; Roberts et al, 1993; Girard et al, 1992; Adnot et al, 1993; Rossaint et al, 1993a).

a) Rees et al (1989) have demonstrated in vivo in the rabbit model that endogenously produced nitric oxide plays a significant role in control of blood pressure via endothelium-dependent vascular relaxation.

a) MECHANISM OF INJURY: Nitric oxide is oxidized in air to form nitrogen dioxide, which then reacts with water in the respiratory tract to form nitric acid. The nitrates and nitrites formed from dissociation of nitric acid cause extensive local and systemic tissue damage (Ramirez & Dowell, 1971). Cyanosis may result (ACGIH, 1992). Death may be due to blockage of gas exchange in lungs (Sittig, 1991).

a) Worsening hypoxemia has been described in a newborn following treatment with nitric oxide inhalation for persistent pulmonary hypertension. Indomethacin use in the mother may have contributed to this response. After 2 minutes of nitric oxide inhalation the preductal oxygen saturation dropped from 82% to 34%. Discontinuation of nitric oxide resulted in a return of preductal oxygen saturation to 80% within 5 minutes (Oriot et al, 1993).
b) A rapid decline in oxygen desaturation has been reported following treatment with inhaled NO for obstructive shock due to massive pulmonary embolism in a 20-year-old woman. Cessation of NO resulted in a rapid initial improvement of oxygenation with baseline levels attained in several hours. It was speculated that gas exchange was worsened in this patient after NO inhalation because the intrinsic pulmonary vasodilating effects of NO undermined a compensated Va/Q equilibrium, leading to an increase in shunt or ventilation/perfusion mismatch and a worsening of oxygenation (Tulleken et al, 1997).

a) SUMMARY: Pulmonary edema is a potential toxic effect of nitric oxide inhalation, primarily due to formation of nitrogen dioxide. Nitric oxide has a markedly less toxic effect on human lung function than does nitrogen dioxide. Nitric oxide is an unstable free radical, and in the presence of oxygen is oxidized to nitrogen dioxide and higher order nitrogen oxides, which can produce pulmonary toxicity (Bouchet et al, 1993; Frostell et al, 1993a; Kinsella & Abman, 1993; Frostell et al, 1993).
b) Nitrogen dioxide is a strong oxidizing gas which is several times more toxic to the lung than nitric oxide, and can initiate lipid peroxidation with resultant cell injury or cell death (Rossaint et al, 1993).
c) Conversion of nitrogen dioxide to nitric acid or nitrous acid could result in severe pulmonary edema or acid pneumonitis (Bouchet et al, 1993).
d) The rate of oxidation of nitric oxide to nitrogen dioxide is dependent upon the time of exposure to oxygen, the concentration of oxygen, and concentration of nitric oxide (Stenqvist et al, 1993).

a) SIGNS/SYMPTOMS: Cough, hyperpnea, and dyspnea may be seen after some delay (Lewis, 1996). Rapid and shallow respirations, coughing and burning in the throat and chest, and physical signs of pulmonary edema may develop. Pulmonary edema may be delayed, occurring 4 to 24 hours following exposure.
b) High concentrations in the range of 60 to 150 ppm may cause immediate coughing and burning in the chest. Concentrations of 200 to 700 ppm may result in death (Sittig, 1991).
c) An asphyxial death due to blockade of gas exchange in the lungs may ensue a few hours after the first evidence of pulmonary edema (Sittig, 1991).

a) Nitric oxide is used therapeutically to induce pulmonary vasodilation, reduce pulmonary arterial pressure, and improve oxygenation in patients with pulmonary hypertension (Beghetti et al, 1995) (Francoise et al, 1995) (Girard et al, 1992).

a) OCCUPATIONAL: Experience with welders has shown that pulmonary damage can occur with chronic exposures too low to produce acute effects (Finkel, 1983).

a) Pulmonary edema, alveolar hemorrhage, bronchiolar mucosa desquamation, and focal inflammatory and mucosal cell plugging of bronchioles were found on histological lung examination of dogs administered toxic levels of nitric oxide and nitrogen dioxide (Shiel, 1967).

a) Emphysematous lesions were produced in mice exposed to 10 ppm nitric oxide for 2 hours/day, 5 days/week for up to 30 weeks. Even though nitric oxide is acutely less toxic then nitrogen dioxide, it was more potent than the latter in inducing emphysematous lesions under similar conditions of exposure (HSDB , 1991).

a) Dogs which were exposed to 0.1% and 2.0% nitric oxide over 5 to 136 minutes and died, experienced a critical reduction in arterial oxygen content which was caused by either methemoglobinemia, low arterial PO2, and/or metabolic acidosis. All dogs which died after 24 minute exposures experienced overt pulmonary edema (Greenbaum et al, 1967).

a) On microscopic examination of rabbits exposed to 5.0 ppm nitric oxide over 14 days, the principal findings were edema of the alveolar-capillary membrane and of the walls of small arteries in the lungs, and distention of the intercellular junction, without an accompanying inflammatory reaction (Hugod, 1979).

a) Exposure to nitric oxide at 2 ppm did not increase the susceptibility of male mice to Pasteurella multocida, but did have a slight effect on female mice (Azoulay et al, 1981).

a) Fatigue, restlessness, lethargy and loss of consciousness may occur following toxic exposures to nitric oxide (Sittig, 1991).

a) Anxiety and mental confusion may occur following toxic exposures (Sittig, 1991).

a) CASE REPORT: A case of paralysis and areflexia of all 4 extremities occurred in an alcoholic 58-year-old woman administered nitric oxide for 15 days postoperatively. Electromyograph showed extensive denervation. Tracheostomy and mechanical ventilation were required for 3 months as muscle function returned. The authors suspected that acute alcohol withdrawal may have left her susceptible to glutamate receptor mediated neurotoxicity induced by nitric oxide (Tsai & Gastfriend, 1995).

a) Neurodevelopmental follow-up of The Neonatal Inhaled Nitric Oxide Study Group (NINOS) reported no increase in neurodevelopmental, behavioral, or medical abnormalities at 2 years of age following inhaled nitric oxide in term and near-term infants (n=85). Neonates greater than 34 weeks gestation and less than 14 days of age with hypoxemic respiratory failure received 20 ppm inhaled nitric oxide during the study (Finer et al, 2000).

a) Nausea may occur (Sittig, 1991).

a) Abdominal pain may occur (Sittig, 1991).

a) A respiratory acidosis may be due to an increase in PaCO2 following respiratory failure (Prys-Roberts, 1967).

a) CASE REPORT: A 65-year-old woman with acute respiratory distress syndrome (ARDS) developed carboxyhemoglobinemia (COHb up to 5.5%) and methemoglobinemia (MetHb up to 2.6%) after she was treated with inhaled nitric oxide (from a gas tank containing 18% NO and 82% N2), at concentrations up to 10 ppm. During the observation, no biological signs were noted suggestive of acute hemolysis, as evidenced by stable values of hemoglobin (9 to 10.5 g/dL) and plasma bilirubin (less than 20 mcmol/L). The patient subsequently developed signs of sepsis with organ failure and circulatory shock and died on day 24 (Rusca et al, 2004).

a) Clinically insignificant methemoglobinemia occurred in normal adults exposed to concentrations up to 128 ppm for 3 hours. One subject given 512 ppm experienced a rapid increase in methemoglobin levels up to 5% at which point the nitric oxide inhalation was stopped (Young et al, 1994).
b) Methemoglobin concentration in an arterial blood sample of 67% was reported in an adult following administration of NO via ventilator settings ensuring administration during inspiratory phase only. Total concentration of nitrates and nitrates in serum was 820 mcmol/L (normal range, 0 to 40 mcmol/L). Methemoglobin concentration decreased to 8% within 1 hour after stopping NO and administering methylene blue (Hovenga et al, 1996).
c) CASE REPORT: Abrupt increase in methemoglobin from 1% to 18.2% was reported on the first day of inhalation therapy with nitric oxide 80 ppm in an infant (Roberts et al, 1997).
d) CASE REPORT: A 65-year-old woman with acute respiratory distress syndrome (ARDS) developed carboxyhemoglobinemia (COHb up to 5.5%) and methemoglobinemia (MetHb up to 2.6%) after she was treated with inhaled nitric oxide (from a gas tank containing 18% NO and 82% N2), at concentrations up to 10 ppm. During the observation, no biological signs were noted suggestive of acute hemolysis, as evidenced by stable values of hemoglobin (9 to 10.5 g/dL) and plasma bilirubin (less than 20 mcmol/L). The patient subsequently developed signs of sepsis with organ failure and circulatory shock and died on day 24 (Rusca et al, 2004).

a) One source has described the formation of methemoglobin as the principal effect of nitric oxide (ACGIH, 1997), while another has downplayed its importance (Lewis, 1996). Following inhalation, NO can combine with hemoglobin to form nitrosylhemoglobin; this is rapidly oxidized to methemoglobin. NO has a high affinity for hemoglobin; binding and formation of methemoglobin is concentration- and time-dependent (Weinberger et al, 2001).
b) Methemoglobinemia may be noted when nitric oxide is present. Clinically significant methemoglobinemia has been reported when nitrous oxide was contaminated with nitric oxide (Clutton-Brock, 1967).
c) CASE REPORT: Inadvertent administration of 110 ppm nitric oxide for about 30 minutes lead to symptoms of nausea and restlessness associated with a methemoglobin level of 19% (Macdonald et al, 1995).
d) CASE REPORT: A dose of NO (80 ppm) for an extended length of time (26 hours) led to the formation of methemoglobinemia of 40%, with deep central cyanosis, in a newborn infant. Following gradual discontinuation of NO over one hour and administration of 1 mg/kg methylene blue, the infant improved (Nakajima et al, 1997).

a) Toxic doses of nitric oxide have been reported to inhibit platelet aggregation and cause an increased risk of bleeding (Weinberger et al, 2001; Joannidis et al, 1996; Ignarro, 1989). Prolongation of the bleeding time has been observed with inhalation of 30 to 300 ppm (15 minutes) in animals and 30 ppm (15 minutes) in healthy subjects (Hogman et al, 1993). This suggests a potential for increased bleeding risk in nitric oxide poisonings.

a) Nitric oxide binds to hemoglobin at the same sites oxygen does, but with an affinity over 1400 times greater. It affects the oxygen dissociation curve, resulting in a reduction in oxygen transport greater than that attributable to pulmonary injury alone (Gosselin et al, 1984).

a) Bleeding time increased from 51 to 72 sec in rabbits after 15 minutes of inhalation of 30 ppm nitric oxide, and from 48 to 78 sec at 300 ppm (Hogman et al, 1994).

a) In animal studies, a concentration of 332 ppm nitric oxide produced 60% methemoglobin after 6 hours (ACGIH, 1986).
b) Nitric oxide was more effective than nitrogen dioxide for inducing methemoglobin in mice (Oda et al, 1980).

a) Nitric oxide is classified as a skin irritant (Lewis, 1996).

a) Cyanosis may be noted as a delayed symptom (Sittig, 1991). This could suggest anoxia or methemoglobinemia or both.

a) Increased risk for several human cancers may be related to elevated levels of endogenous nitric oxide in chronic bacterial, viral, and parasitic infections (Liu & Hotchkiss, 1995).

a) Monitor pulmonary function tests in symptomatic patients.

a) Rescuers must be protected from inhalation by self-contained breathing and from contact by plastic gloves.

a) Exposure is usually via inhalation. Nitric oxide is relatively non-toxic when compared with nitrogen dioxide.

a) Treatment for mild and moderate symptoms consists of predominantly decontamination, removal from exposure, and symptomatic and supportive care. All patients with a significant exposure (either inhalation, eye, dermal, or oral exposure) should be carefully observed for the possible development of delayed clinical signs and symptoms.

a) Patients who develop severe toxicity with hypotension should be treated first with IV fluids, if hypotension persists, the addition of vasopressors (eg, dopamine or norepinephrine) may be required.

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

a) These recommendations apply to patients with MINOR chemical burns (FIRST DEGREE; SECOND DEGREE: less than 15% body surface area in adults; less than 10% body surface area in children; THIRD DEGREE: less than 2% body surface area). Consultation with a clinician experienced in burn therapy or a burn unit should be obtained if larger area or more severe burns are present. Neutralizing agents should NOT be used.

a) After initial flushing with large volumes of water to remove any residual chemical material, clean wounds with a mild disinfectant soap and water.
b) DEVITALIZED SKIN: Loose, nonviable tissue should be removed by gentle cleansing with surgical soap or formal skin debridement (Moylan, 1980; Haynes, 1981). Intravenous analgesia may be required (Roberts, 1988).
c) BLISTERS: Removal and debridement of closed blisters is controversial. Current consensus is that intact blisters prevent pain and dehydration, promote healing, and allow motion; therefore, blisters should be left intact until they rupture spontaneously or healing is well underway, unless they are extremely large or inhibit motion (Roberts, 1988; Carvajal & Stewart, 1987).

a) TOPICAL ANTIBIOTICS: Prophylactic topical antibiotic therapy with silver sulfadiazine is recommended for all burns except superficial partial thickness (first-degree) burns (Roberts, 1988). For first-degree burns bacitracin may be used, but effectiveness is not documented (Roberts, 1988).
b) SYSTEMIC ANTIBIOTICS: Systemic antibiotics are generally not indicated unless infection is present or the burn involves the hands, feet, or perineum.
c) WOUND DRESSING:
d) DRESSING CHANGES:
e) Analgesics such as acetaminophen with codeine may be used for pain relief if needed.

a) The patient's tetanus immunization status should be determined. Tetanus toxoid 0.5 milliliter intramuscularly or other indicated tetanus prophylaxis should be administered if required.

a) NEONATES (GREATER THAN 34 WK GESTATION): The recommended dose is 20 parts per million (ppm) via inhalation for up to 14 days or until resolution of oxygen desaturation; MAX dose is 20 ppm, as higher doses are associated with significantly increased risk of methemoglobinemia (Prod Info INOmax(R) inhalation gas, 2013).
b) In a prospective, observational study in children with acute respiratory distress syndrome and pulmonary hypertension, the maximal dose response occurred at doses between 20 and 40 ppm (Nakagawa et al, 1997); in another prospective study, the optimal dose was 20 ppm in neonates (with additional persistent pulmonary hypertension) and 5 to 10 ppm in children (Demirakca et al, 1996).

1) Nitric oxide

a) TWA: 25 ppm (30 mg/m(3))
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

a) IDLH: 100 ppm
b) Note(s): Not Listed

a) 8-hour TWA: