Article Text

PDF

Pulmonary hypertension in patients with COPD: NO treatment?
  1. J Pepke-Zaba,
  2. N W Morrell
  1. Pulmonary Vascular Diseases Unit, Papworth Hospital, Papworth Everard, Cambridgeshire CB3 8RE, UK
  1. Correspondence to:
    Dr N W Morrell, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Box 157, Hills Road, Cambridge CB2 2QQ, UK;
    nwm23{at}cam.ac.uk

Statistics from Altmetric.com

The application of “pulsed” NO combined with LTOT may have a role in treating pulmonary hypertension secondary to COPD.

Following the identification of nitric oxide (NO) in 1986 as “endothelium derived relaxing factor”, there has been an exponential growth in our understanding of the physiological role of NO culminating in the award of a Nobel Prize, and the naming of NO as “molecule of the decade”.1 Considerable research has subsequently been devoted to understanding the role of this molecule in vascular biology in general, and the pulmonary vascular system in particular.

NO is an unstable radical with a low blood gas partition coefficient. For decades NO was considered an environmental contaminant produced by bacteria and internal combustion engines. Believed to be highly toxic, it appeared an unlikely candidate for a major role as a biological mediator. However, within the last 15 years it has become clear that endogenously produced NO is ubiquitous in mammalian systems, playing an important role in both health and disease: in the regulation of blood pressure and flow, inflammatory responses, and neurotransmission. Insight into these physiological roles has led to its use as a therapeutic agent in a number of clinical settings.

There are ample data to support a major role for NO in the regulation of tone and vascular remodelling in the normal and diseased pulmonary circulation. Endothelial NO contributes significantly to the normally low pulmonary vascular tone,2 and dysfunction of endothelial NO release has been documented in patients with chronic obstructive pulmonary disease (COPD).3,4 Although nitro-vasodilatation (acting through the intracellular generation of NO) has been used effectively since the 1800s for systemic arterial dilatation (delivered sublingually, orally, and intravenously), the prospect of selective pulmonary nitro-vasodilatation only became evident in the early 1990s.5 Treatment with inhaled NO has subsequently been applied in a variety of lung diseases which have in common a degree of pulmonary vascular endothelial dysfunction and/or abnormalities of gas exchange based on low ventilation/perfusion (V/Q) ratios. This includes the use of NO in patients in intensive care, neonates with persistent pulmonary hypertension, and in postoperative settings where NO is used to reduce pulmonary vascular resistance and/or improve oxygenation—for example, pulmonary thromboendarterectomy, heart and lung transplantation, acute lung injury.

In the lungs, one important molecule with which NO reacts is oxyhaemoglobin (HbO2). The affinity of HbO2 for NO is 106 times greater than its affinity for oxygen.6 Oxidative reactions of NO with haemoglobin largely limit the effects of inhaled NO to the lung vasculature. However, there are reports that high concentrations of inhaled NO have peripheral vascular effects when peripheral endothelial NO synthesis is blocked, suggesting that at least a portion of inhaled NO survives long enough to reach tissue remote from the lungs.7 The major immediate breakdown products of NO in human plasma are inactive nitroxides such as nitrite (NO2). The rate of this reaction increases exponentially with the concentration of both oxygen and NO.8 This has several consequences. Firstly, low NO concentrations or oxygen free environments permit relatively long term persistence of NO. Secondly, the therapeutic efficacy of inhaled NO may not rise dramatically with increased doses as the more NO given, the faster it is oxidised.9 In fact, higher doses of NO result in a relatively greater proportion of toxic products with little incremental yield of intact NO. Finally, the rapid inactivation of inhaled NO in an oxygen rich environment is what makes NO a selective pulmonary vasodilator. Inhalation delivers NO to the pulmonary resistance vessels before it is oxidised. The seconds before the inhaled NO enters the systemic circulation are enough for its breakdown by interaction with oxygen and haemoglobin.

Pulmonary hypertension secondary to COPD is probably more common than is generally appreciated. Right heart catheterisation studies suggest a prevalence of up to 40% in selected series of patients with severe COPD.10,11 A degree of pulmonary hypertension was observed in 55% of consecutive respiratory outpatients using Doppler echocardiography.12 The presence of pulmonary hypertension in patients with COPD is associated with increased mortality11,13 and an increase in exacerbation rate and length of hospital stay, independent of the degree of airflow obstruction.14 Although often inferred, the precise contribution of pulmonary hypertension to exercise limitation or quality of life in stable COPD patients is unknown. Mean pulmonary artery pressure in patients with COPD is typically mild (in the region of 25 mm Hg) at rest but can rise to abnormally high levels on exercise.

At present there are no specific treatments recommended for the reduction of pulmonary artery pressure in COPD. Although long term oxygen therapy (LTOT) improves survival in hypoxaemic patients with COPD, it has a negligible effect on pulmonary haemodynamics. Clearly, other factors in addition to alveolar hypoxia contribute to the development of pulmonary hypertension in COPD. For example, remodelling of the pulmonary vessels is present in many patients with mild COPD who are not hypoxaemic and appears to be related to cigarette smoking.15

There are several reports of the use of inhaled NO in patients with stable COPD.16–19 NO inhalation alone may worsen V/Q relationships and exacerbate systemic hypoxaemia while lowering pulmonary vascular resistance. However, when NO is delivered to well ventilated alveolar units with fast time constants, the deleterious impact on gas exchange is avoided.19 This effect can also be achieved by using “pulsed” delivery of NO where spikes of NO are added at the beginning of inspiration. The addition of oxygen to NO further prevents hypoxaemia.

The study reported in this issue of Thorax by Vonbank et al20 shows that long term use of pulsed NO with oxygen leads to sustained improvement in pulmonary haemodynamics without worsening hypoxaemia in patients with stable COPD. Benefits of the pulsed method include the reduced formation of nitrogen dioxide and methaemoglobinaemia. A further safety issue that needs to be addressed is whether discontinuation of long term inhaled NO can lead to severe rebound pulmonary hypertension. Although the results presented by Vonbank et al show promise, it remains to be determined whether pulsed NO/oxygen treatment will lead to an improvement in exercise tolerance, quality of life, and survival in patients with hypoxaemic COPD. Potential disadvantages of the approach include the delivery system and monitoring systems necessary to ensure accurate dosing and safety. In addition, long term gas therapies are far from convenient for the patient. NO reduces pulmonary vascular resistance by increasing cyclic GMP levels in vascular smooth muscle cells. This effect can also be achieved by inhibition of the enzymes that metabolise cyclic GMP. Inhibitors of the type 5 cyclic GMP phosphodiesterase such as sildenafil may have some selectivity for the pulmonary circulation, and it remains to be seen whether these drugs administered orally may have an effect equivalent to inhaled NO.

The application of “pulsed” NO combined with LTOT may have a role in treating pulmonary hypertension secondary to COPD.

REFERENCES

View Abstract

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Linked Articles

  • Airwaves
    Wisia Wedzicha