Belfast 1997
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Delivery Systems & Clinical Indications For Nitric Oxide. Introduction.

GG Lavery,

Belfast

A decade ago. NO was noteworthy only as an impurity in nitrous oxide, a constituent of tobacco smoke or an urban pollutant. Yet in the period 1992-1996, over 7000 clinical papers containing nitric oxide as a key word were published. This explosion in interest follows the discovery that NO is a ubiquitous biological mediator and is responsible for both intracellular and intercellular signaling in many organisms including man^1,2.

Synthesis of NO.

In man, NO is synthetised from arginine by the action of nitric oxide synthetases (NOS), a group of complex proteins which catalyze both oxidative and reductive processes. One of the locations of NOS activity is the vascular endothelium. NO, generated by endothelial NOS (eNOS), induces relaxation of vascular smooth muscle by activating guanylate cyclase and increasing intracellular cyclic guanosine monophosphate (cGMP).

Nitric oxide is highly reactive with a half-life of only a few seconds. Haemoglobin inactivates NO by (i) binding it to form nitrosohaemoglobin and (ii) by promoting the degradation of NO to nitrate and nitrite. During its fleeting existence, NO interacts with the haem moiety in guanylate cyclase thus activating the enzyme which is responsible for formation ofcGMP. It is the rise in cGMP which modifies cellular function often by influencing intracellular calcium concentration.

Therapeutic use of NO

Several commonly used drugs exert their effects by generating NO. The best examples are nitrates used to cause venodilatation and a decrease in preload in patients with cardiac pain. Such drugs work mainly on the venous side of the circulation since veins do not normally possess eNOS and thus are more sensitive than arterioles to agents which generate NO.

Inhaled NO.

In humans exhaled air contains measurable levels of NO. The function of this endogenously-released NO in the lung is to modulate pulmonary vascular tone and hypoxic pulmonary vasoconstriction. In 1988, inhalation of NO was shown to reduce pulmonary artery pressure" and was subsequently used to treat primary pulmonary hypertension, e.g.persistant pulmonary hypertension of the newbom - PPHN and also the arterial hypoxaemia and pulmonary hypertension associated with acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). At levels of< 80 ppm, NO appears to act as a selective vasodilator acting only in those areas of the lung which are ventilated. Thus. unlike intravenous prostaglandins, it does not increase ventilation/periusion mismatch or shunt fraction. Its short half-life and local metabolism mean that pulmonary vasodilatation can be achieved without any associated systemic vasodilatation and arterial hypotension. Such a treatment strategy, however, is not without problems and the toxic effects of NO include methaemoglobinaemia, production of NO2 and the peroxynitrate ion, bleeding diathesis and rebound pulmonary hypertension.

The use of inhaled NO has yet to be shown to improve outcome in ALI/ARDS but is the most promising treatment modality of the last two decades and undoubtedly does improve some of the life-threatening abnormalities in these conditions.

Delivery Systems for Inhaled NO

The original system used to deliver NO to patients was based on a Douglas bag in which NO and 02 were mixed. Due to a propensity for N02 formation with this arrangement it is no longer acceptable. Any NO delivery system must be capable of delivering an accurate and stable concentration of NO over the clinical range. Such a system may be considered under the following headings; source of gas, method of delivery, monitoring and scavenging.

Source of NO

NO is usually supplied in a large cylinder (green with gold shoulders). If this is not stabilized .ideally by mounting it on the delivery/detector system, its bulk and weight may constitute a hazard to staff or patients. A cylinder of pure NO would need a flow rate of only 0.2 ml/min to achieve a NO concentration of 20 ppm in a 10L/min gas flow. Such low flows are difficult to measure with sufficient accuracy and so NO is usually supplied in N3 at a concentration of 1000 ppm. With this source, a NO level of 20 ppm would take a flow rate of 200 ml/min which is much easier to deliver accurately. NO (1000 ppm in N2) is stable at room temperature and 1 atm. At higher pressures NO2 and N2O may be formed in the cylinder.

Over long periods NO will corrode many metals and also adversely effects plastics and rubber. Such effects may lead to standard reducing valves on NO cylinders leaking thus causing inadvertent atmospheric pollution. Reducing valves, flow-meters and other metal connectors in contact with NO should be made of stainless steel. Leaks have been detected in some units only when several staff members complained of headaches at work (due to cerebral vasodilatation). If a separate NO detector is used to monitor NO concentrations near the cylinder source, leaks will be detected earlier.

Method of Delivery

NO readily combines with Oz to form N02. The amount formed depends on the concentration ofO; (patient dictated), the square of the concentration of NO (clinician dictated) and the contact time of the two gases (dictated by design of delivery system). Toxic concentrations of NO2 can be produced in less than 25s when NO (lOOppm) isnmixed with 100%02. In 1988 the "safe" limit for N02 exposure was said to be 5ppm. Today it is recommended to keep N02 concentrations below 1ppm. Once inhaled, the affinity of NO for haemoglobin is so strong that there is no further reactivity with 02.

The simplest delivery method is a continuous flow of NO into the inspiratory port of the ventilator circuit. Such a system increases the period of contact between 02 and NO since the gases can mix during the (static) expiratory phase of the ventilatory cycle. There is also evidence of gas streaming and uneven delivery of NO with continuous flow systems. Synchronised injection of NO during the inspiratory phase is a preferable delivery method since it reduce the contact period and minimize NO2 production. The bolus effect is also reduced. Synchronized injection systems require rapidly reacting sensors and flow valves.

Monitoring

During inhaled NO therapy, it is mandatory to continuously monitor NO, N02 and 02.

Abrupt reduction in inspired NO concentration can result in major reduction in oxygenation and rises in PAP. Any delivery system should also allow clinicians to make incremental changes in NO concentration. NO and NO; may be detected using chemiluminescence or electrochemical detectors. The former are superior in many ways and are frequently used in industry. In the clinical environment, however, electrochemical detectors, despite their relative lack of accuracy, seem more appropriate. Newer electrochemical machines use active sampling and water traps to reduce the adverse effects of moisture and pressure/flow sensitivity which bedeviled early detectors of this type.

Accurate detectors will only be of use if the sampling site is appropriate. NO and NO2

must be sampled as near the patient as possible since this is where the longest exposure of NO to 0; will occur. Since NO will be avidly taken up within the lungs, it is important that the sampling site is not subject to contamination with expiratory gas. Alveolar NO/NO2

concentration would be the ideal parameter to monitor. Use of NO will also result in the generation ofmethaemoglobin. It is practice in our own unit to measure methaemoglobin levels 4 hourly and to maintain a level below 4% by reducing inhaled NO (if possible) or by the administration ofmethylene blue intravenously as a 0.5 -1.0 mg/kg bolus.

Scavenging

Guidelines for ventilation in NHS premises require 10-12 air changes per hour It is felt that if this standard is achieved then scavenging is not necessary. In other situations, environmental levels of NO and NO2 should be monitored and scavenging is mandatory if exposure limits are exceeded. Scavenging can be active (expensive) or passive (into wall suction system). Soda lime which contains potassium permanganate is an effective scavenger. Activated charcoal and alumina have been suggested as potentially better scavengers. Charcoal must be dry and therefore should be preceded by a HME filter.

Conclusion

NO is a very significant molecule in human physiology. By augmenting (or reducing) its concentration in various tissues we may be able to improve the condition of critically ill patients. No gaseous agent, administered regularly to patients, requires the accuracy of delivery associated with NO. Indeed no agent has such a narrow therapeutic index. We need to understand the principles behind the delivery systems used with this agent if significant patient morbidity is to be avoided.

Further Reading.

1. Moncada et al, 1991. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacological Rev. 43,109-42.

2. Vallance & Collier, 1994. Biology and clinical relevance of nitric oxide. Brit. Med. J. 309.453-457.

3. Fink & Payen, 1996. The role of nitric oxide in sepsis and A1WS: synopsis of a roundtable conference held in Brussels on 18-20 March 1995. Int. Care. Med. 22, 158-165.

4. Skimming , JW, Blanch PB, Banner MJ 1997. Behavior of nitric oxide infused at constant flow rates directly into a breathing circuit during controlled mechanical ventilation. Crit.Care Med. 25, 1410-1416.

POSTOPERATIVE INHALATIONAL ANAESTHESIA

JM Murray

At a remarkably early stage of anaesthesia's development, John Snow demonstrated a profound insight about many, now accepted, aspects of his subject — such as the need for efficient vaporisers and the relevance of saturated vapour pressures ("elastic forces"), the inverse relationship between effect and blood-gas solubility and the assessment of relative potencies of inhalational agents.

The subsequent development of apparatus used to deliver volatile anaesthetics has run in parallel with the pharmacokinetics of the drugs themselves - however, the principles outlined by Snow still hold true today. Thus any vaporiser is simply a device for adding clinically useful concentrations of anaesthetic vapour to a stream of carrier gas. This apparatus can either be extremely simple or technologically complex while achieving the same end result.

The introduction into clinical practice of inhaled anaesthetics with blood gas solubility coefficients approaching or equaling that of nitrous oxide represents a significant advance over currently available "fluranes". Sevoflurane and desflurane have desirable kinetic profiles allowing for both a rapid induction and emergence from anaesthesia. Their great advantage over other inhaled anaesthetics is the impressive flexibility that these drugs offer enabling a rapid adjustment of the alveolar concentration during use. Clinical concentrations of volatile anaesthetic agents are normally added to a breathing system via a sophisticated vaporiser which is situated in the fresh gas inflow or "out-of-circle". The placement of the vaporiser in this situation is perceived as standard. Liquid anaesthetic can be injected directly into the breathing system where the minute ventilation is available for vaporisation. This paper describes a new system which has been devised that allows computer control of a pre-set end tidal concentration of volatile anaesthetic for sedation of patients in intensive care. Liquid drug is injected directly into the inspiratory limb of any breathing system by way of a device which ensures immediate vaporisation of the volatile agent.

Septic shock remains a major cause of death in intensive care units. Patients with sepsis syndrome often require mechanical ventilation in order to improve oxygen delivery¹. Sepsis is frequently accompanied by myocardial dysfunction. Haemodynamic investigations have revealed the characteristic pattern of cardiac performance during septic shock consists of reduced left and right ventricular ejection fractions, increased end-diastolic and end-systolic volumes of both ventricles, and normal stroke volume; heart rate and cardiac output are elevated². Systemic vascular resistance is also reduced as control of the tone of the peripheral vasculature is altered³.

Mechanical ventilation is often necessary in critically ill patients to improve oxygen delivery and haemodynamic stability. Sedation is required for most of these patients. It helps to allay anxiety, encourage sleep, facilitate controlled ventilation, and minimise the distress caused by unpleasant procedures, but should still allow a tranquil awareness of the patients' surroundings⁴.

Sedative drugs used should be rapidly acting so that sedation can be easily controlled and of short duration, to allow rapid recovery for neurological assessment and early weaning from ventilatory support. They should have minimal cardiorespiratory depressant effects, no influence on the biodegradation of other drugs, and be eliminated by pathways that are independent of renal or hepatic function. This should result in a short elimination half-life without active metabolites. The ideal sedating agent does not exist at present.

Propofol is widely for the above purpose. It has a short duration of effect and may be administered by infusion. Recovery from propofol is usually rapid. However, it occasionally has pronounced cardiodepressant effects. Propofol reduces systemic vascular resistance, stroke volume and cardiac output, although the effect on heart rate is small. In normocarbic human subjects, cardiac index is not altered by concentrations of sevoflurane up to 1.66 MAC in oxygen. Indirect evidence ofmyocardial depression is provided by the fact that stroke volume and cardiac index are unchanged or reduced despite increased preload and reduced afterload. Systemic vascular resistance is reduced.

Prolonged infusion of propofol may increase serum triglycerides⁵. In paediatric intensive care, reversible neurological sequelae⁶ and several deaths ⁷ have been reported following its prolonged use. Continuous intravenous infusion increases the volume load on the patient.

Volatile anaesthetic agents have been used to provide sedation in ICU⁸. Isoflurane administered at low concentrations, (0.1-0.6%), has been shown to provide sedation similar to propofol⁹ and superior to midazolam¹⁰. Sevoflurane has a blood / gas partition coefficient of 0.7; thus, the alveolar concentration rises rapidly towards the inspired concentration, leading to rapid induction of anaesthesia. Variation of depth of sedation, and recovery from sedation can occur rapidly. Because of its physico-chemical properties, sevoflurane may be a suitable agent for sedation in intensive care.

Elimination is independent of normal hepatic and renal function, and hence organ failure will not be expected to prolong the clinical effects of volatile agents. They do not increase the patients' volume load. Sedation with isoflurane in mechanically ventilated patients has been shown to lead to lower catecholamine levels than with midazolam¹¹; excess catecholamine secretion is associated with increased mortality and morbidity following cerebrovascular accidents and acute head injury. Sevoflurane, a new, commercially available, inhalational anaesthetic agent, has physicochemical and pharmacological properties consistent with suitability for provision of sedation in critically ill patients. Prolonged administration of fluorinated volatile anaesthetics may produce significant concentrations of fluoride ion; previously implicated in fluoride ion nephrotoxicity. These concerns relating to modern agents have now been clarified due to absence of intra-renal metabolism despite serum fluoride concentrations above 50μ molar¹².

In summary, this paper will outline the main advantages of sedation with volatile agents highlighting recent knowledge of their metabolism during prolonged use. In addition, the different technical manoeuvres necessary for administration of volatile anaesthetics with sophisticated ventilators and the problems that this poses for efficient drug delivery will be discussed.

References:

1. Kaplan R, Sahn S, Petty T. Incidence and outcome of the respiratory distress syndrome in Gram-negative sepsis. Archives of Internal Medicine 1979;139:867-869.

2. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parillo JE. Profound but reversible myocardial depression in patients with septic shock. Annals of Internal Medicine 1984;100:483-490.

3. Groeneveld ABJ, Nauta JP, Thijs LJ. Peripheral vascular resistance in septic shock: its relation to outcome. Intensive Care Medicine 1988; 14:141-147.

4. Shapiro BM. Sedation for mechanically ventilated patients: Back to basics please! Critical Care Medicine 1994:22(6):904-906.

5. Carrasco G, Molma R, Costa J, Soler JM, Cabre L. Propofol vs

midazolam in short- medium- and long-term sedation of critically ill patients. Chest 1993;103:557-564.

6. Trotter C, Serpell MG. Neurological sequelae in children after prolonged propofol infusion. Anaesthesia 1992;47:340-342.

7. Parke TJ, Stevens JE, Rice ASC, Greenway CL, Bray RJ, Smith PJ, Waldman CS, Verghese C. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: Five case reports. British Medical Journal 1992;305:613-616.

8. Spencer EM, Willatts SM. Isoflurane for prolonged sedation in the intensive care unit; efficacy and safety. Intensive Care Medicine 1992;18:415-421.

9. Millane TA, Bennett ED, Grounds RM. Isoflurane and propofol for long-term sedation in the intensive care unit. A cross-over study. Anaesthesia 1992:47:768-774.

10. Kong K, Willatts S, Prys-Roberts C. Isoflurane compared with midazolam for sedation in the intensive care unit. British Medical Journal 1989:298:1277-1280.

11. Kong KI, Willatts SM, Prys-Roberts C, Harvey JT, German S. Plasma catecholamine concentration during sedation in ventilated patients • requiring intensive therapy. Intensive Care Medicine 1990;16:171-174.

12. Kharasch ED, Hankms DC, Thummel KE. Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane toxicity. Anesthesiology 1995; 82: 689-699.                    •

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