Tag: gas delivery

The clinical uses of inhaled nitric oxide (iNO) have evolved over the decades as more and more data reveal its benefits (and potential benefits) for a range of cardiopulmonary disorders. By Charles V. Pollack, Jr, MD, FACEP, FAHAClinician Scientist, Department of Emergency Medicine, University of Mississippi Medical CenterChief Medical Officer, Vero Biotech Introduction Nitric oxide (NO) is a compound produced by many cells of the body, including the vascular endothelial cells of the lung. In particular, NO relaxes vascular smooth muscle by increasing intracellular levels of cyclic guanosine 3’,5’- monophosphate (cGMP), which then leads to vasodilation of the pulmonary capillaries. Beyond the lung, NO is an essential signaling molecule and is also involved in a number of important and diverse physiologic processes throughout the body, including modulating immunological host defense and inhibiting platelet aggregation. The effects of exogenous NO are best understood in lung physiology. Inhaled nitric oxide (iNO) produces selective pulmonary vasodilation and reduces the pulmonary vascular resistance (PVR) associated with pulmonary hypertension (PH), preferentially increasing the partial pressure of arterial oxygen (PaO2) in better ventilated areas of the lung. This action redistributes pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios towards regions with normal ratios. Fortunately, because of efficient scavenging and inactivation by hemoglobin, iNO has a minimal effect on the systemic vasculature and therefore only rarely causes hypotension, in important contrast to intravenously infused vasodilators. Charles V. Pollack, Jr, MD, FACEP, FAHA Vero Biotech The vasodilator effects of endogenous, endothelial-derived NO were first recognized in 1987, and the first description of iNO for the treatment of PH was presented at the American Thoracic Society conference in 1988, by Higenbottam, who delivered the talk “Inhaled endothelium-derived relaxing factor (EDRF) in primary pulmonary hypertension.”1 In 1991, Lancet published the study, showing that 40 parts per million (ppm) iNO selectively reduced pulmonary artery pressure with no significant changes in systemic pressure.2 The pluripotential therapeutic impact of iNO has been and continues to be further described since then, but while it is currently used in many clinical settings in children and adults, the only FDA-approved indication of iNO, which was granted in 1999, is to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO) in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure (HRF) associated with clinical or echocardiographic evidence of pulmonary hypertension, termed “PPHN” for persistent pulmonary hypertension in the newborn. How Is iNO Used in the Hospital Today? Approximately 35,000 term and near-term neonates require mechanical ventilation because of HRF, which is commonly caused by PPHN.3 Avoiding high levels of inhaled oxygen and airway pressures is important in this population to limit the incidence of mortality, chronic lung disease (bronchopulmonary dysplasia, or BPD), and serious neurological complications. The numerous risks associated with ECMO including hemorrhage, infection, ischemia, neurological deficits, are well-documented. Studies have shown that iNO, usually administered at a starting dose of 20 ppm, can improve these outcomes in many infants. With iNO available in the hospital, however, there have been notable increases in use outside the neonatal intensive care unit, particularly in the cardiac catheterization laboratory and in the perioperative management of patients undergoing major cardiothoracic surgery. In the cath lab, iNO at 20-40 ppm is used for vasoreactivity testing during right heart catheterization to guide therapy for PH.4 Once the PH diagnosis is confirmed by pulmonary artery (PA) pressure measurements, 100% oxygen is administered to the patient for five minutes, followed by reassessment of PA pressures. If pressures normalize with oxygen alone, further testing need not be performed, and the patient’s PH is treated simply with supplemental oxygen. If the oxygen challenge does not reduce PA pressure, acute vasodilator testing with iNO is often performed, and if PA pressures decrease, the patient is considered an “acute responder.” This designation guides the path to possible transplant in some cases, and further chronic PH therapeutics, which may include calcium channel blockers or various combinations of prostacyclin pathway agonists, endothelin receptor antagonists, and NO-cGMP enhancers. However, acute exacerbations may prompt administration of iNO—this time as therapy, not as a diagnostic challenge. In the perioperative setting, iNO at 10-30 ppm is used to support oxygenation in patients undergoing surgeries up to and including heart transplant, lung transplant, and implantation of left ventricular assist devices (LVADs).5 In cardiac applications, including transplants, PH can lead to right-sided heart failure and early death. Inhaled NO can reduce right ventricular stroke work while not reducing systemic blood pressure. In lung transplantation, iNO is administered in an effort to attenuate ischemia-reperfusion injury, which is an early cause of transplant rejection. Similarly, after LVAD placement, iNO-driven reductions in RV afterload can result in increased left ventricular (LV) filling, LVAD flow, and overall cardiac output. In orthotopic liver transplantation, studies have shown that iNO decreases hepatocyte apoptosis, limits increases of hepatic transaminases, enhances recovery of coagulation factors, and be a treatment modality for hepatopulmonary syndrome. Additional Uses of iNO Require Further Study Another potential use of iNO therapy, for which past studies have had inconsistent and conflicting results, is for acute respiratory distress syndrome (ARDS).6,7 Pulmonary hypertension is a hallmark of ARDS, as is V/Q mismatch; the PH contributes to pulmonary edema and RV overload. All of these pathophysiologic features point to a good likelihood of benefit from iNO, and many early studies showed improvement in pressure and oxygenation parameters, but no improvement on survival rates among patients with ARDS. These studies, however, predated the use of lung-protective ventilation that has since been shown to be beneficial in these patients. More recent studies using this ventilation approach and iNO, mostly in pediatric patients, have shown clearer benefit as measured by both days of mechanical ventilation and ECMO-free survival. Evidence showing a benefit of iNO in ARDS in adults continues to accumulate slowly, but large randomized trials are needed to determine a potential impact on survival. Safety Considerations There are few known safety concerns about the use of iNO. A primary issue is the phenomenon of “rebound PH” upon abrupt decease in dose or discontinuation of iNO, which can lead to hypoxia, decreased cardiac output and systemic hypotension, and increased intrapulmonary right-to-left shunting. Weaning protocols for the dose of iNO coupled with responsive oxygen supplementation greatly reduce the risk of rebound. Although all unusual, clinicians should be aware of these other safety issues that have been related to the use of iNO: Methemoglobinemia: iNO can combine with hemoglobin to form nitrosylhemoglobin, which is rapidly oxidized to form methemoglobin (metHb), which when present in excessive quantities (generally > 15-20% of total hemoglobin) can cause tissue hypoxia. The enzyme metHb reductase converts metHb back to hemoglobin that is available for oxygen carrying. Because neonates have reduced activity of this enzyme, they may be at greater risk for developing clinically significant methemoglobinemia during iNO therapy than are adults. If identified before evidence of hypoxia (such as cyanosis) develops, downward titration of iNO usually allows the methemoglobinemia to clear, but if levels are particularly high or the patient is notably symptomatic, a dose of 1–2 mg/kg of methylene blue intravenously is advised.8Accumulation of nitrogen dioxide (NO2): NO is unstable in air and will be directly converted to NO2, which is toxic to the respiratory tract at exposures above 5 ppm. Interestingly, most of the toxicologic work on NO2 was performed because it is a major constituent of urban air pollution. At toxic doses, NO2 induces airway inflammation and reactivity, as well as alterations in surfactant metabolism. Newer iNO delivery systems monitor for NO2 at the patient interface.9Acute kidney injury (AKI): some studies have shown a risk of AKI during iNO therapy, particularly during perioperative periods of substantial physiologic stress. The mechanism of iNO-related AKI is unclear, and other studies have shown little to no risk of AKI or need for new renal replacement therapy after iNO treatment. Perhaps some care in duration of exposure should be exercised in patients who already have renal insufficiency.10Effects on platelet aggregation and bleeding time: in addition to modulating vascular tone, NO inhibits platelet adherence to endothelial cells as well as platelet-to-platelet aggregation.11 Studies on platelet activity and bleeding time have shown conflicting results; one study of neonates treated with iNO at 40 ppm for PPHN showed a prolonged bleeding time but normal in vitro platelet function. In some adults treated with iNO for ARDS, there was evidence of prolonged bleeding times, inhibition of platelet aggregation, and reduced P-selectin expression and fibrinogen binding, though there was no consistent clinical correlate to these findings.11 Potential for Out-of-Hospital iNO Use While iNO clearly reduces elevated PVR in most cases of acute pulmonary decompensation due to PH, more sustained use has been inadequately studied. There are reports of therapeutic use of iNO...

Tag: gas delivery

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