A 2-year-old Hispanic female with ARDS benefited from nitric oxide after surfactant administration.
In both neonates and older children, the pathophysiology of ARDS is characterized by interstitial and alveolar lung edema. This leads to increased intrapulmonary shunting and ventilation-perfusion (V/Q) mismatching, with impaired pulmonary gas exchange and pulmonary artery vasoconstriction. Right ventricular failure with concomitant low cardiac output and resulting multiple organ dysfunction may be the consequence.1 Disorders associated with ARDS include aspiration, drug toxicity, hematologic disorders, hemodynamic disorders, infection, inhalation injury, metabolic disorders, neurological disorders, obstetrical/gynecological disorders, shock, and trauma.2
Selective pulmonary vasodilators, optimal positive end-expiratory pressure (PEEP), permissive hypercapnia, fluid management, exogenous surfactant replacement, and alternative modes of ventilation are currently used at our institution to support pediatric patients with ARDS. Individual protocols have been developed for the use of inhaled nitric oxide and surfactant replacement in the treatment of ARDS. The time of intervention is suggested, but is ultimately left to the discretion of the critical care physician. The potentially synergistic effect of these therapies had not previously been our focus.
Surfactant replacement is considered for patients with decreasing pulmonary compliance, refractory hypoxemia (Pao2/fraction of inspired oxygen [Fio2] of less than 250), high ventilating pressures, and excessive PEEP. Destruction of the alveolocapillary membrane causes damage to type II pneumocytes, inhibiting surfactant production. This, in turn, has a devastating effect on pulmonary compliance (leading to atelectasis and V/Q mismatching). Our goals are to increase pulmonary compliance, increase the number of functional alveoli, reduce V/Q mismatching, and prevent the iatrogenic injuries frequently caused by mechanical ventilatory support.
Many times, inhaled nitric oxide therapy is used in patients with ARDS, who have varying responses. Our guidelines for the use of nitric oxide in pediatric patients with ARDS include
- an Fio2 of more than or equal to 0.6;
- a PEEP of more than 10 cm H2O;
- a Pao2/Fio2 of less than 100; and
- a Murray score3 of more than or equal to 2.5.
Hypoxemia and hypercarbia cause an increase in pulmonary hypertension. Our goal in using nitric oxide therapy is to dilate the pulmonary capillaries selectively, thus decreasing intrapulmonary shunting and increasing arterial oxygenation.
A 2-year-old Hispanic female was transferred to our institution from an outside hospital for an acute aspiration event and a new onset of bronchiolitis with respiratory failure. Her past history included tracheostomy secondary to tracheobronchomalacia. At the outside institution, she had been decannulated and had been intubated using a 5.0 mm uncuffed endotracheal tube due to difficulties encountered in providing mechanical ventilation via tracheostomy tube. After 36 hours of mechanical ventilation and management of ARDS, she was transferred to the Children’s Hospital of Philadelphia for further evaluation.
On arrival, her ventilatory requirements were 189 mL/kg corrected exhaled minute ventilation, positive inspiratory pressure of 37 cm H2O, PEEP of 15 cm H2O, and Fio2 of 1. These settings yielded a pH of 7.28, Paco2 of 67.5 mm Hg, Pao2 of 77.5 mm Hg, bicarbonate level of 31.3 mmol/L, base excess of 10.3, Pao2/Fio2 of 78, and oxygenation index (OI) of 30. She had a heart rate of 145 beats per minute, blood pressure of 120/75, and temperature of 37.7°C. Initial laboratory tests revealed hemoglobin of 14 g/100 mL, white blood cell count of 21,000/mL, platelet count of 299,000/mL, calcium level of 8.5 mg/dL, magnesium level of 2.6 mg/dL, phosphorus level of 3.5, sodium level of 145 mg/dL, potassium level of 4.5 mEq/L, blood urea nitrogen level of 12 mg/dL, creatinine level of 0.3 mg/dL, and glucose level of 120 mg/dL. She tested negative for respiratory syncytial virus.
Her preadmission chest radiograph revealed a ground-glass appearance. Further investigation of her lung condition included a CT scan, which showed bronchiectasis in the right lower lobe and evidence of old abscesses in the left lower lobe. Atelectasis was evident in the left and right upper lobes. Her right middle lobe was hyperinflated.
Management of her cardiovascular status briefly included an esmolol infusion to control episodes of hypertension. While receiving esmolol, she exhibited end-expiratory wheezes and decreased expired tidal volumes, but no change in blood pressure. The drug was, therefore, discontinued.
Management of the patient’s pulmonary status included alternative positioning, aggressive pulmonary toilet, and bronchodilation with albuterol every 2 hours, ipratropium bromide every 6 hours, and a terbutaline infusion. She was sedated and paralyzed using fentanyl, midazolam, and pancuronium infusions. Prone positioning was tried at the outside hospital and did not improve gas exchange. The patient was placed with her right side down in an attempt to increase ventilation to her left lung. This also failed to produce the anticipated improvement in her gas exchange. She was then placed in a rotation/percussion bed, and kinetic therapy was initiated.
The patient’s Fio2 could be reduced from 1 to 0.65 during the beginning stages of her illness, but she later deteriorated, with Pao2 levels in the mid to low 40s. This was accepted as long as she did not develop metabolic or lactic acidosis; she was assessed continuously to ensure adequate tissue oxygenation. At this time, the extracorporeal membrane oxygenation team was consulted and placed on standby status.
On the third day of mechanical ventilation, nitric oxide therapy was started using 20 ppm. We monitored the patient’s blood gas levels for any significant response (a 20% change in the Pao2/Fio2 or OI is considered a favorable response at our institution). Her initial Pao2/Fio2 was 78 and her OI was 30. Within the first hour of nitric oxide use, the Pao2/Fio2 decreased to 72 and the OI increased to 31. After 2 hours, the Pao2/Fio2 had decreased to 60 and the OI had significantly increased to 37; 6 hours later, the Pao2/Fio2 remained at 60 and the OI had decreased to 35. Nitric oxide therapy was stopped after no further response was noted.
On the fifth day of mechanical ventilation, the patient’s Pao2/Fio2 was 71 and her OI was 37. A 32-mL dose of bovine surfactant was given via fiberoptic bronchoscope. The patient tolerated this procedure well. Her endotracheal tube was also changed to a 5.0 mm cuffed nasal tube due to a continued leak around her uncuffed tube and to increasing ventilatory demands. A day after surfactant- replacement therapy, her Pao2/Fio2 was 72 and her OI was 35. Two additional doses of surfactant were given via intratracheal catheter. No significant response was noted in the Pao2/Fio2 or OI after surfactant administration.
On the sixth day of mechanical ventilation, another trial of nitric oxide was given after surfactant administration. Some of the literature4 suggests that improvement follows the combined use of nitric oxide and surfactant therapies. Within the first hour of this trial, the Pao2/Fio2 increased to 97 (a 27% improvement) and the OI was 26 (a 30% improvement from her baseline). After 4 hours, the Pao2/Fio2 was 97 and the OI was 26. After 8 hours, the Pao2/Fio2 was 90 and the OI was 27; 13 hours later, the Pao2/Fio2 was 98 and the OI was 22, indicating a 28% improvement in the Pao2/Fio2 and a 41% improvement in the OI.
After a 2-month admission to the pediatric intensive care unit, this patient, now requiring minimal mechanical ventilatory support, was transferred to a nearby rehabilitation hospital.
Review of this patient’s course of illness and response to therapeutic interventions seems to indicate that inhalation of nitric oxide after surfactant administration produced a more favorable response than nitric oxide or surfactant alone.
The vascular endothelium produces nitric oxide from a naturally occurring amino acid, l-arginine. Nitric oxide activates soluble guanylate cyclase, stimulating production of cyclic 3’,5’-monophosphate, which results in vascular and smooth-muscle relaxation. The exposure of constricted blood vessels to nitric oxide results in their prompt relaxation, which lasts 3 to 5 seconds after the removal of nitric oxide.5 Once in the blood, nitric oxide is rapidly taken up by hemoglobin and metabolized.
The effectiveness of nitric oxide in ARDS remains controversial. Although there have been many reports of improved short-term outcomes, there is no evidence that nitric oxide has any impact on mortality.6
The toxic effects of inhaled nitric oxide include methemoglobinemia and the inhalation of nitrogen dioxide. It is important to monitor methemoglobin levels to make sure that they do not rise above 5%. We monitor levels prior to treatment, an hour after the start of therapy, and once per day as long as the patient continues to receive nitric oxide. If methemoglobin levels should approach 5% or nitrogen dioxide levels exceed 1 ppm, nitric oxide would be discontinued. We have not encountered these conditions while using nitric oxide at the current dose of less than or equal to 20 ppm.
Surfactant, dipalmitoylphosphatidylcholine (DPPC), is produced by type II pneumocytes and reduces the surface tension of the alveoli. Injury to type II pneumocytes reduces the production and turnover of surfactant.7 Abnormalities in the production, composition, and function of surfactant probably contribute to alveolar collapse and to gas-exchange abnormalities.7 The disadvantages of surfactant loss include decreased lung compliance, areas of atelectasis, and alveoli filled with transudate.8
The pharmacological activity of surfactant results from the combined action of three synthetic components: DPPC, cetyl acid, and tyloxapol. DPPC acts rapidly to decrease surface tension. Cetyl alcohol facilitates the dispersion and absorption of DPPC onto the air-liquid interface of the alveoli. Tyloxapol provides the product with a hydrophilic agent that allows for reconstruction of the lyophilized powder.9 Exogenous surfactant replacement may help reduce iatrogenic injuries from mechanical ventilation, but it may not improve oxygenation by itself in ARDS.
The effects of nitric oxide are limited to areas of the lung that are well ventilated. Since nitric oxide does not recruit alveoli, surfactant should be delivered before the administration of inhaled nitric oxide. If it is possible to increase the amount of surface area available for gas exchange and decrease the amount of dead space ventilation, nitric oxide should have a better effect on the pulmonary vasculature and should decrease the amount of intrapulmonary shunting.
Why did the patient fail to respond to the first dose of nitric oxide? Pao2/Fio2 and OI worsened during the first trial of nitric oxide in this patient with bilateral atelectasis. Does this support the theory that intrapulmonary diffusion of nitric oxide to the non-ventilated areas of the lung increase intrapulmonary shunting?6 It has been suggested that patients with severe hypoxemia have a lower nitric-oxide-induced increase in Pao2, which was the case of this patient.10
Future studies are needed on the use of nitric oxide and surfactant as synergistic modalities. The role of nitric oxide in ARDS is still unclear. Is early intervention (at the beginning of acute lung injury) beneficial? At what Pao2/Fio2 should clinicians intervene? Should lung-injury scoring be used to guide practice? Large, multicenter studies need to be performed to answer these questions. If it can be shown that there is a decrease in the mortality rate for pediatric patients with ARDS attributable to the use of nitric oxide and surfactant together, then protocols should be implemented to support their combined use. N
Shawn Colborn, RRT, is a staff therapist, Department of Respiratory Care, Children’s Hospital of Philadelphia; Theresa Ryan Schultz, RRT, RN, is a clinical research specialist and pediatric intensive care unit staff nurse at the hospital; and Angela Mittman, RRT, is a clinical specialist in the hospital’s neonatal intensive care unit.
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