Inhaled nitric oxide: are the safety issues being addressed?

Inhaled nitric oxide: are the safety issues being addressed? Chris Jones Interest in the therapeutic uses of Nitric Oxide (NO) has gathered pace over the last decade. It is no exaggeration for the UK Guidelines on the Use of Inhaled Nitric Oxide (Cuthbertson et al. 1997) to say that 'the use of inhaled nitric oxide in the UK has become commonplace'. The index of the third edition (I 990) of TE Oh's notable Intensive Care Manual carries no reference to it. Yet, from its origins in obscure research, the discovery of NO has promised the development of therapies which might include the revolutionary transformation of approaches to the treatment of septic shock. It also holds promise in the treatment of acute respiratory distress syndrome (ARDS). It is in this context that this discussion will seek to raise fundamental questions about the health and safety aspects of this substance.

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INTRODUCTION

Chris Jones RGN, Edge Hdl University College, Aintree Complex, Fazakerley Hospital, Longmoor Lane, Liverpool L9 7AL, UK [email protected] (Requests for offpnnts to CJ) Manuscript accepted 19 October 1998

The rise o f nitric oxide (NO), declared Molecule o f the Year by the American Academy for the Advancement o f Science m 1992, has been remarkable. For instance, if one enters the search term 'A1KDS' into a Medline search for the years 1993-1997 one will be notified o f 1612 items. If one enters 'Angina', one will be notified o f 4529 papers. 'Nitric oxide' raises 19976 items. Adverts for nursing posts have started to appear in nursing publications requiring a working knowledge o f N O in the practice setting (Nursing Times 98/051).

HOW DOES NITRIC OXIDE WORK? N O is a gas which is commonly found m various types o f atmospheric pollution. Cigarette smoke

Intenswe and Crmcal Care Nursing (I 998) 14, 271-275 © 1998Harcourt Brace& Co Ltd

contains relatively high concentrations o f it (Zapol & Hurford 1994). N O is produced in the cells by the enzyme nitric oxide synthase. T h e chemical origins o f N O involve an intimidating sequence o f biochemical events. Nevertheless, N O can best be understood by its effect; it causes the prevention o f cellular calcium flow and precipitates vaso-dilatation. There is an excellent discussion o f the physiology o f N O in W o o d r o w (1997). N O causes the relaxation o f blood vessel walls and causes a drop in vascular resistance, one o f the determinants o f blood pressure. Nurses have been using this property o f N O for many years. Nitroglycerine and sodium nitroprusside have been used in critical care areas for many years for their vasodilatory properties. For much o f this period, it was not understood that the mode o f action o f these substances was the release o f N O . Other roles o f N O include a central role in immunology. It is a cytotoxic agent used by activated macrophages to destroy invading organisms. It is also a messenger molecule in the central and peripheral nervous system. It is the intention o f this paper to discuss the apphcation o f N O as an inhaled gas in the treatment o f A R D S , although there are many other potential applications. 39V£',: " L Y ;:~C~:U~';;

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WHAT APPLICATIONS ARE THERE FOR NITRIC OXIDE IN THERAPEUTICS? Septic shock There are many applications for this gas in human therapeutics. It was originally discovered during the search for a substance from the walls o f blood vessels which caused vasodilatation. Endothelial derived relaxant factor (ED1KF) was eventually discovered to be N O (Zapol 1996). W h a t is more, ED1KF was seen to play a role in the vasodilatation occurring in septic shock. Some outflow o f N O was discovered to be part o f the normal function o f phagocytosis. N O , a highly toxic gas, was part o f the defence mechanism o f a host under attack from an organism. N O disabled the organism as it was destroyed. The problem with the unrestrained release o f N O was that it caused an uncontrolled vasodilatation which compromised the body's capacity to maintain blood vessel resistance and therefore blood pressure. If N O causes the drop in systemic vascular resistance which lies at the heart o f septic shock, then perhaps N O blocking agents w o u l d be an alternauve way o f encouraging vasoconstriction and preventing multi-system failure (Petros et al 1994). This would be a

272 Intensiveand Critical Care Nursing revolutionary breakthrough in the treatment o f septic shock, which has hitherto relied on the somewhat rough and ready use o f noradrenaline. Noradrenaline, a potent vasoconstrictor, may raise blood pressure but when observable tissues like nose and toe tips become blue or black if high volumes of noradrenaline are used, it is reasonable to question whether vital organs are being evenly perfused. Blocking the effect o f overproduced N O holds out at least a promise o f another approach to the treatment o f septic shock (Petros et al 1994).

Acute respiratory distress syndrome Interest in N O for acute respiratory distress syndrome (ARDS) is based upon its function as a vasodilator. N O is used as an inhaled gas to dilate the bed o f the pulmonary circulation (Zapol 1996). This, in turn, brings down the pressure in the pulmonary arteries which is one o f the main problemanc features of ARDS. The gas is inhaled via the ventilator circuit and passes through the alveoli, dilating the capillaries o f the pulmonary artery (Cuthbertson et al 1997). The potential advantage of N O is very apparent. Alternative methods for the control of pulmonary hypertension, such as intravenous nitrates or prostacyclin, have the disadvantage o f simultaneously reducing the systemic blood pressure (Sitbon et al 1995). Frequently, systemic hypotension is also a problem for patients in intensive care units (ICUs). Therapy aimed at the control of hypertension in the lungs may cause a drop in blood pressure in the kidneys and other vital organs as an unwanted consequence. The elegance o f inhaled N O as an approach to the control o f pulmonary hypertension is that the N O molecule will retain its effect passing through the muscle wall of the blood vessel. W h e n it emerges and meets the haem portion o f the red blood ceils it ceases to exert its vasodilatory properties (Gaston et al 1994). Therefore, when the gas reaches the general circulation as methaemoglobin it has no effect on blood pressure. Unfortunately, there is considerable controversy about whether the treatment works, whether it works with some groups o f patients more than others, or whether its apparent benefits are transient and 'cosmetic' (Payen 1998).

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H O W IS NITRIC O X I D E DELIVERED? As an atmospheric pollutant N O and its derivative nitrogen dioxide (NO2) is a major

byproduct o f car exhausts. It is a gas which has been implicated in the rising tide of juvenile asthma which seems to be a feature of life in the developed countries. As a therapy N O is given in small doses through a specially modified ventilator circuit. Its mode o f delivery has been extensively discussed elsewhere (Cuthbertson et al 1997). Because it is a toxic substance, it has been recommended that in poorly ventilated units the gas is scavenged from the circuit in a similar way to anaesthetic gases such as nitrous oxide in operating theatres. As well as recommending scavenging techniques in enclosed spaces, the guidelines also point out that National Health Service (NHS) estate guidelines say that if the I C U delivering N O was built to modern standards o f ventilation and air flow routine measurement of ambient N O need not be performed (Cuthbertson 1997).

W H A T SPECIFIC HEALTH A N D SAFETY MEASURES ARE R E C O M M E N D E D FOR STAFF U S I N G NITRIC OXIDE? There are recommendations about the health and safety of operatives using N O . They are contained in the U K Guidelines on the Use of Inhaled Nitric Oxide. The problem is that the health and safety aspects are a rather undeveloped part of the report and even the part o f the paper devoted to health and safety considerations is split between the patient and the operative. As a guideline to the health o f the person who is by the bedside there are several issues which are not addressed. This is not exclusively a U K phenomenon. A US paper published on the World Wide Web from Duke University Medical School in the USA points to similar problems there (Charlton & Spainhour 1996). In a survey of ICUs in the USA, they found grossly conflicting policies, practices and even doses involved in the use o f inhaled N O .

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W H A T PROBLEMS M I G H T THERE BE W I T H NITRIC OXIDE? One hopes that there will be no problems with N O but information on high-risk groups using the substance is hard to find if it exists at all. Possible areas of concern might include: 1. Should pregnant nurses be working alongside a patient breathing N O ? This issue is not addressed by the U K guidelines, which

Inhalednitricoxide 273 is surprising. It is not so long ago that theatre nurses were reporting misgivings about working in atmospheres polluted by nitrous oxide because o f a perceived rise in the rate o f spontaneous abortion. In the D u k e U n i versity survey o f hospitals using N O , units were divided half and half on the question o f whether pregnant nurses should be so employed (Charlton & Spainhour 1996). 2. Is N O mutagenic? The U K guidelines raise the question o f mutagenesis without answering the question. The most that is said is that 'further data are awaited on the potential role o f N O and N O 2 in mutagenesis' (Cuthbertson et al 1997). Although Gaston et al (1994) argue that 'Both endogenous and exogenous Nitrogen Oxides ... form products ... with frank mutagenic potential (nitrosamines).' 3. Should an asthmatic nurse be caring for a patient breathing N O ? Given that oxides o f nitrogen have been implicated in the rise o f asthma in the population, it would seem a reasonable precaution to keep asthmatic nurses away from ventilators piping in N O but no such recommendation exists. Even though N O is k n o w n to become a pulmonary irritant above a certain dose, the safety precautions seem to apply to the patients only. There is no recommendation even from Duke University. Indeed, leading authorities on the subject present conflicting opinions. Gaston et al (1994) argue that 'Notwithstanding the evidence for increased N O production in asthma, exogenous organic nitrates may exert bronchodilator effects in asthmatic patients ... but they do not exclude the possibility that N O exacerbates the asthmatic state by promoting inflammation'. Zapol and Hurford (1994) on the other hand state that 'Preliminary chnical studies suggest that inhaled N O may have a bronchodilator effect in some patients with asthma'. 4. Are there any other potential problems associated with N O ? N O is k n o w n to influence clotting function in patients (Frostell cited in Gaston et al 1994). This might be o f interest to a pregant nurse or a nurse w h o is already the victim o f a coagulopathy.

S H O U L D THE P A T I E N T BE C A R E D FOR IN A SIDE ROOM? It is possible that a patient with A R D S might become infected with a communicable organism. In the normal state o f affairs the patient might be transferred into a side ward. This may have an effect on the concentrations o f gas and

the air clearance. Cuthbertson et al (1997) give little information other than the raw parts per million (ppm) scores for N O concentration. In any case where nurses are to be looking after patients on N O they should be familiar with the signs o f N O toxicity in case there should be a leak or monitoring equipment failure and somebody receives a toxic dose.

W H Y IS THE I N F O R M A T I O N A B O U T USER H E A L T H A N D SAFETY SO SKETCHY? There appears to be an unspoken inference applied to inhaled N O , which is as follows: • I F N O is a c o m m o n atmospheric pollutant (Table 1), • if roadside levels o f N O are higher than therapeutic levels (Table 1), • if intensive care workers walk along the roadside with no ill effects, • then it must be all right for them to w o r k alongside a patient receiving inhaled N O . This argument carries some weight in c o m m o n sense. The m a x i m u m measured level o f N O in an I C U is l p p m (Cuthbertson et al 1997). This is infinitesimal compared to the m a x i m u m dose in a cigarette, which has been measured at 1000ppm (Zapol 1994). But while there may be a small background level o f N O (Table 1), this does not establish that there are not local pockets where exposure is considerably higher or that even low-grade exposure does not have some ill effect. During the change in the ventilator circuit, during physiotherapy, or during suction, one can imagine that local levels o f N O are considerably higher than 1 ppm. Even then, one can envisage that delivery systems can fail and release high concentrations o f N O in the bedside area. N o r does this carry reassurance for the nurse who is exposed to low-grade toxicity over a long period. Zapol and Hurford (1994) point out that: 'Although the US Occupational Safety and Health Administration has set an N O exposure limit o f 2 5 p p m w h e n breathed for 8 hours a day in the workplace, few l o n g - t e r m studies o f N O toxicology have been reported.' If this inference is the basis o f the poor or non-existent research done on the health and safety aspects o f N O on operators then it should be stated explicitly. Medicine, after all, is not short o f examples o f where well-meaning enthusiasm for a novel technique has led to corners being cut for users' health and safety.

274

Intensiveand Critical Care Nursing

Table ! Differing levels quoted for E d ~ Date

nitric oxide in various contexts

NO

NO 2

Cited in

Source of citation

Recommended maximum levels of environmental exposure

1988

COSHH*

25ppm

3ppm

Cuthbertson et al. (1997)

1994

CDC/NIOSH ~

25ppm

5ppm

Zapol & Hurford (I 994)

Dose ranges used in animal studies

1994

80- 100ppm

Young

1991

5-80ppm

Frostell

1995

2-40ppm

Mulnier & Evans

Woodrow(1997)

Therapeutic levelsofinhaled N O usedfor children

1995

5-20ppm

Bellamy & Semple

1994

3-10ppm

Abman

Woodrow (1997)

Therapeutic levels of inhaled N O used for adults

1996

20M0ppm

Results from a survey of US hospitals using inhaled NO

Charlton & Spainhour (I 996)

Recommended dose for inhaled N O

1997

20-40ppm

Conclusion of consensus report

Cuthbertson et al. (1997)

Measured concentrations of background N O in intensive care units

1997

Cuthbertson et al. (I 997)

I ppm

Atmospheric levels of N O and N O z in cities

Date measured

City

1993

Sheffield

1994

Birmingham Liverpool Glasgow Manchester

Measured by 100ppm Francome & Marks

48ppm 75ppm 94ppm 170ppm

Woodrow (1997)

Problems associated with inhaled N O in animals and humans

Date

Reported by

Problem

1996

Dizziness and nausea in nurses

1988

GrolI-Knapp et al.

1982

Kagawa

1993

Mercer et al.

N/K

Frostell

50ppm > I ppm NO/NO2 mixture 5ppm N/K

Charlton & Spainhour (I 996)

Impaired performance of remembered tasks in rats Measurable fall in lung performance in beagles

Gaston et al. (1994)

Thickening of alveolar capillary membrane in rabbits Bleeding diathesis

* Control of Substances Hazardous to Health Centers for Disease Control NatI 0 nal Institute for Occupational Safety and Health N/K, not known

~

The early years o f X-rays are littered with examples of what we would regard as horrific laxity with radiation. Porter (1997) illustrates this point well when he relates that: 'Therapeutic enthusiasm outran caution, and the dangers o f radiotherapy were determined at great cost to patients and radiographers alike (many of the latter lost their lives) ... Fluoroscopes went on being employed quite casually in shoe shops and X-rays in ante

natal clinics. As late as the 1940s, benign menstrual bleeding was sometimes treated with X-rays and radium.' Closer to the present day, there has been the concern about the exposure of theatre nurses to the anaesthetic gas N O . There has also been a transformation in the attitude to gluteraldehyde with previously lax attitudes tightened up to account for health and safety worries (Day 1995).

Inhaled nitric oxide

275

I f i n d i v i d u a l nurses o u g h t to b e c o n c e r n e d

safety u s i n g this gas are n o t b e i n g asked.

a b o u t u s i n g i n h a l e d N O i n t h e absence o f firm

M o r e o v e r , it is v e r y h a r d to find a n y i n f o r m a t i o n r e g a r d i n g t h e s e basic questions. It is n o t h a r d to f i n d i n f o r m a t i o n c o n c e r n i n g t h e effect o f N O o n rat n e u r o c h e m i s t r y . H o w e v e r , asking whether NO should be used by a pregnant n u r s e seems to p r e s e n t f e w answers a n d these, i n t u r n , are i n c o n s i s t e n t .

a n d r e l e v a n t guidelines, t h e n trusts o u g h t to b e e v e n m o r e c o n c e r n e d . I f N O is a substance that carries n o risk to its users, t h e r e is n o n e e d for c o n c e r n , b u t i f t h e r e are risks to a n asthmatic nurse, to p r e g n a n t nurses or to a n u r s e k e p t in a c o n f i n e d space t h e n trusts m i g h t b e at t h e b e g i n n i n g o f a n u n p r e d i c t a b l e course o f h e a l t h a n d safety litigation. Already t h e r e is m e n t i o n i n t h e literature t h a t practitioners r u n t h e risk o f litigation i n u s i n g a substance w h i c h does n o t carry a licence a n d w h i c h m a y o n l y b e used o n a n a m e d p a t i e n t basis ( C u t h b e r t s o n et al 1997). W o o d r o w (1997) goes o n e step f u r t h e r a n d outlines legal j e o p a r d y facing t h e n u r s e w h o administers N O : ' N i t r i c O x i d e s h o u l d ... b e c o n s i d e r e d as a n e x p e r i m e n t a l drug, a n d nurses w h o use it m u s t accept t h e i r professional a c c o u n t a b i l i t y i n a c c o r d a n c e w i t h t h e c o d e o f professional conduct.' Trusts u s i n g an u n l i c e n s e d substance w h i c h goes o n to h a r m nurses m i g h t face e n o r m o u s p r o b l e m s justifying t h e i r u n b r i d l e d e n t h u s i a s m to an already suspicious public.

CONCLUSION It is n o t t h e i n t e n t o f this p a p e r to d a m p e n e n t h u s i a s m for this e x c i t i n g a n d i n n o v a t i v e a p p r o a c h to a r a n g e o f c o n d i t i o n s w h i c h , e v e n n o w , carry a d e p r e s s i n g l y h i g h m o r t a l i t y . M e d i c a l a d v a n c e has f r e q u e n t l y b e e n m a d e b y p r a c t i t i o n e r s t a k i n g a m e a s u r e d a m o u n t o f risk b u t , similarly, it has to b e o f c o n c e r n to nurses using inhaled NO that questions about their

REFERENCES Cuthbertson B H, Delhnger P, Dyar O J et al 1997 UK guidelines for the use of inhaled nitric omde therapy in adult ICUs Intensive Care Medicine 23:1212-1218 Charlton F D, Spainhour V 1996 Inhaled Nitric Oxide Its role m cnucal care. DUMC TSU HOME PAGE 3200/ACU-nitnc Day M 1995 Indecent exposure. Nursing Times 91 (20): 18 Frostell Cited in Gaston et al 1994 Gaston B, D razen J M, Loscalzo J, Stamler J S 1994 The biology ofmtrogen oxides m the airways. American Journal of Respiratory Care Medicine 149:538-551 Oh T E •990 Intensive Care Manual. Butterworth, London Payen D 1997 Is nitric oxide therapy a 'cosmeuc' therapy m acute respiratory &stress syndrome? American Journal of Respiratory Cnucal Care Medicine 157: 1361-1362 Petros A, Lamb G, Leone A et al i994 Effects ofa mmc oxide synthase inhibitor m humans with septic shock. Cardiovascular Research 28 (1): 34-39 Porter R 1997 The Greatest Benefit to Mankind. A Medina1 History of Humamty from Antiquity to Present Day. Harper Colhns, London, p. 608 Sltbon O, Brenot F, Denoean A et al 1995 Inhaled nitric oxade as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. American Journal of Respiratory Care Medicine 151:384-389 Woodrow P 1997 Nitric oxide: some nursing lmphcanons. Intensive and Critical Care Nursing 13 (2): 87-92 Zapol W M, Hurford W E 1994 Inhaled nitric oxide in adult respiratory distress syndrome and other lung diseases. Advances in Pharmacology 31: 513-530 Zapol W M 1996 Inhaled Nitric Oxide. Acta Anaestheslologica Scandinavma Suppl 109:81-83