Eur J Cardiothorac Surg 1998;14:488-493
© 1998 Elsevier Science NL
Beneficial effects of inhaled nitric oxide in hypoxaemic patients after coronary artery bypass surgery1
B. Prendergasta,
D.H.T. Scottb,
P.S. Mankada
a Royal Hospital For Sick Children NHS Trust, 9 Sciennes Road, Edinburgh, EH9 1LF, UK
b Royal Infirmary, Edinburgh, UK
Received 5 April 1998;
received in revised form 28 July 1998;
accepted 11 August 1998.
Corresponding author. Tel.: +44 131 5360675; fax: +44 131 5360623; e-mail: pankaj.mankad@ed.ac.uk
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Abstract
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Objective: Arterial oxygenation may be impaired in the early period after open-heart surgery, with an associated increase in ventilation time, morbidity and hospital stay. We tested the hypothesis that inhaled nitric oxide could be a useful therapeutic adjunct in this setting. We sought to establish clinical benefits (if any), safety and the appropriate dose range of inhaled nitric oxide therapy in hypoxaemic patients after coronary artery bypass graft surgery. Methods: Forty patients who satisfied our definition of post-operative impaired oxygenation were prospectively randomised. The treatment group (n=20) received nitric oxide in addition to ventilatory support. While the control group (n=20) was managed only by conventional ventilatory support. Cardio-respiratory parameters and clinical outcome measures were compared. Results: We determined the optimum concentration of inhaled nitric oxide as 20 ppm in the majority (60%) of patients. Treatment improved arterial oxygenation (8.4±1.4 kPa before, 11.8±1.5 kPa after 4 h, P<0.001) and this benefit was sustained with lower oxygen fractions required at 24 h (P<0.001). A significantly shorter period of mechanical ventilation was required in the treatment group (mean ventilation hours 67.0±5.9 vs. 85.0±6.5, P<0.05), although the study did not have the power to distinguish differences in ITU or overall hospital stay. Nitrous oxide and met-haemoglobin levels did not rise appreciably. Conclusion: We have established the safety and efficacy of inhaled nitric oxide, at a dose of between 10 and 30 ppm, in this group of patients. We suggest that nitric oxide and a delivery system are useful adjuvants in a cardiac surgical intensive care unit.
Key Words: Nitric oxide • Coronary artery bypass graft • Hypoxaemia
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Introduction
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Prolonged mechanical ventilation after coronary artery bypass (CAB) surgery is undesirable, however it is one of the most frequently observed complications and is known to be associated with a significant hospital mortality
[1]. Extended ventilatory support is frequently required because of poor arterial oxygenation
[2]. Many mechanisms contribute to post CAB hypoxaemia, but disturbance of nitric oxide activity may have an important role. Chronic endothelial dysfunction is central to the pathogenesis of atherosclerotic disease
[3]. Furthermore, ischaemia-reperfusion and the inflammatory response to cardio-pulmonary bypass are associated with an additional acute impairment of endothelial function
[4]. Endothelial dysfunction is characterised by deficient intrinsic nitric oxide release not only in the pulmonary vasculature but also in the upper airways. Nitric oxide is synthesised in the upper airways and auto-inhaled by healthy persons
[5], contributing a physiological `aerocrine' regulation of pulmonary ventilation-perfusion matching
[6] and other beneficial effects, for example the up regulation of ciliary motility
[7]. These processes are interrupted by intubation and mechanical ventilation. This interruption of natural nitric oxide auto-inhalation by artificial ventilation might be a reason for a ventilation-perfusion mismatch in the lung resulting in poor arterial oxygenation
[8].
Although inhaled nitric oxide (iNO) has been the subject of intense scientific and clinical investigation for some 10 years, its precise physiological and therapeutic roles are yet to be defined
[9]. Whereas the role of iNO in reducing pulmonary vascular resistance after cardiac surgery is becoming quite clearly defined, investigation of its effect, if any, on post-operative arterial hypoxaemia has produced variable results. Under different circumstances, several investigators have shown little beneficial effect of iNO on arterial oxygenation after cardiac surgery
[10]
[11]
[12]
[13]. While more recently Bender et al.
[14] have shown that iNO improves oxygenation in hypoxaemic patients after cardiac surgery. However, half of their group comprised of paediatric patients who had surgery for congenital heart defects, and the remaining seven patients were adults who were almost exclusively transplant recipients. None of the patients had coronary artery bypass surgery. The objective of this randomised controlled trial was to explore the role of iNO treatment in a group of patients, with impaired oxygenation after routine coronary artery bypass surgery, establishing a dose range and assessing both immediate and longer-term effects.
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Materials and methods
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All patients underwent surgery and anaesthesia according to our current practice, with cardiopulmonary bypass at moderate hypothermia (core temperature 30–32°C) and flow rates of 2.4 l/minxm2. Cardiac arrest was induced using 1 litre of cold crystalloid antegrade plegia, with a further 500 ml delivered between completion of each distal anastomosis.
We defined impaired arterial oxygenation as occurring in a mechanically ventilated patient, when 2 h after his return to the intensive care unit; arterial oxygen tension was (paO2)<10.0 kPa, with inhaled oxygen fraction (fiO2)
0.70 and positive end expiratory pressure (PEEP) of 10 cmH2O. Such patients were considered candidates for this trial if they were haemodynamically stable (i.e. with a mean systemic blood pressure65 mmHg and no mechanical support).
With local ethical committee approval forty patients were identified and randomised to control or treatment groups. Demographic variables were recorded (age, sex) and a profile obtained of pre-existing pulmonary function (smoking history, current bronchodilator therapy, and pulmonary function before operation).
Patients in the control group received routine ventilatory support (sedation, without paralysis, volume control ventilation with minute volume adjusted to achieve paCO2 of approximately 6.0 kPa and PEEP-10 cmH2O). The treatment group was managed similarly with the addition of nitric oxide (Linde gas UK) to the ventilatory circuit; its concentration continuously monitored by a fuel cell (Micro Medical UK) sited close to the patient. In both groups pulmonary artery thermodilution catheters were sited and hourly recordings were made of haemodynamic parameters, including cardiac output, pulmonary artery pressures and arterial blood gases. After 24 h, these indices were collected at four hourly intervals. Ventilation was weaned with regard to these parameters, according to the protocol described below. Additionally intermittent (no less than four hourly) measurements were made of nitrogen dioxide within the breathing circuit (by fuel cell) and of circulating met-haemoglobin (co-oximeter). The clinical outcome measures, requirement for mechanical ventilation, step down from ITU and discharge from hospital, were recorded.
The dose of nitric oxide was individually selected for each patient during the first hour of the study, balancing apparent efficacy with a desire to administer minimal concentrations. Based on our own and published experiences
[15] we arbitrarily adopted 40 ppm as the upper limit of iNO therapy. We determined each patient's response, in terms of arterial oxygenation, over a range of doses (10, 20, 30 and 40 ppm) to this maximum, and assumed a plateau beyond this. A series of curvilinear dose-response curves were thus obtained.
Fig. 1
shows a typical dose (nitric oxide)–response (arterial oxygenation) curve obtained in one of the patients. From each such curve we defined an individual's maximum initial response (MIR), thereafter each patient continued to receive the smallest dose of nitric oxide that achieved two thirds (the greater part) of this maximum initial response.
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Fig. 1. A typical dose response record (arterial oxygenation, paO2 (kPa) plotted against nitric oxide concentration (ppm)). The maximum initial response (MIR) in terms of improved oxygenation is defined, (assuming a plateau beyond 40 ppm). The treatment dose is selected to achieve two thirds of this response. This patient received 20 ppm inhaled nitric oxide throughout the remaining trial period.
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During the first 4 h no changes were made to ventilatory parameters. Attempts were made to wean ventilation after this period, based on blood gases obtained at the times stated above, with the following protocol applied to both groups. Inspired oxygen concentration was reduced by 10 percentage points if possible whilst maintaining paO2>10.0 kPa. When fiO2=0.40, PEEP was removed. Other aspects of ventilatory support (sedation, minute volume) were adjusted as required. Patients were then considered for extubation. Where patients returned from theatre with inotropic support, this was similarly left unchanged for four hours. After this interval dosage was reviewed with each set of study-parameters, weaning where possible but ensuring mean systemic blood pressure65 mmHg. Strictly identical criteria were followed in both groups.
Patients were considered for step down from the ITU at morning and early afternoon rounds. A period of cardio-respiratory stability was required, but this was not formalised. Discharge from hospital was according to our local practice, which is at any point beyond 5 post-operative days subject to satisfactory clinical progress. The study did not influence these decisions, which were for the most part taken by staff blinded to the study.
Statistical analysis (t-test (paired) or chi squared) was used as indicated in the Table 1Table 2Table 3. Certain variables: changing oxygen requirements and systemic oxygenation; ventilation times, step down time from ITU and discharge from hospital, are unlikely to be normally distributed and so are compared by non-parametric (Wilcoxon rank) analysis.
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Table 1. Pre-operative and intra-operative characteristics of the control and treatment groups were statistically similar
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Table 2. Comparison of arterial oxygenation, cardiac output, mean pulmonary arterial and mean systemic arterial pressures: at the time of randomisation and after 4 h
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Results
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Table 1 summarises both the pre- and intra-operative characteristics of control and treatment groups. Preoperative respiratory state is reflected as positive cigarette smoking history (within 5 years), concurrent bronchodilator therapy and spirometry. In all respects, the two groups were statistically similar.
Dose response
In 19 patients from the treatment group, paO2 exceeded 10.0 kPa (fiO2<0.7) at 1 h with 16 patients receiving nitric oxide doses of 10 or 20 ppm, and three patients receiving 30 ppm. One patient showed little benefit even receiving 40 ppm and a dose of 20 ppm was administered empirically. No patients developed clinically significant levels of nitrous oxide or met-haemoglobin during the trial.
Cardio-respiratory changes
Initially indistinguishable, at 4 h there was a statistically significant improvement in arterial oxygen tension in the treatment group when compared to changes seen over this period in the control group. (Table 2). This was sustained, with a lower oxygen requirement seen at 24 h (
Fig. 2
). Cardiac output increased with time in both the control and the treatment group, but there was no statistical difference between the groups. Mean arterial pressure and mean pulmonary pressures showed no significant variation over the study period (Table 2).
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Fig. 2. Changes in oxygen requirement (inspired oxygen fraction) between randomisation and 24 h. Fourteen patients in the control group still received 70% oxygen at 24 h. The majority of patients within the treatment group had been weaned to 60% oxygen at this point, with five patients making even more progress. The treatment group shows a statistically significant (Wilcoxon rank sum) improvement.
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Clinical outcome
The treatment group required mechanical ventilation for a shorter period than controls (mean ventilation hours 67.0±5.9 vs. 85.0±6.5 h, P<0.05). Ventilatory status was the limiting factor for ITU step-down, and times were shorter for the treatment group, however this failed to reach statistical significance. There was no significant difference in hospital discharge times. Except for one patient who subsequently suffered a sternal dehiscence, adverse events were confined to chest infections, with positive sputum culture common in both groups (no statistical difference) (Table 3).
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Discussion
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Inhaled nitric oxide in low doses (10–30 ppm) has a clinically beneficial effect on post cardiotomy hypoxaemia, as manifest by early improvements in oxygen requirement and mechanical ventilation time. This study did not have the power to establish a significant trend in terms of shortening the step down time from ITU, but offers support to the use and safety of this therapy.
The aetiology of arterial hypoxaemia after cardiopulmonary bypass is multifactorial and may reflect both cardiovascular and pulmonary compromise. Low cardiac output is associated with impaired arterial oxygenation
[16]. Pulmonary factors include pre-existing lung disease, mucous plugging and atelectasis
[17]. These conditions respond to conventional management. However arterial oxygen saturation is particularly sensitive to intrapulmonary ventilation-perfusion (V/Q) imbalance. High inspired oxygen fractions, introduced to improve the clinical condition, may further exacerbate V/Q mismatching
[18]. Furthermore systemic administration of nitric oxide donors (with non-selective activity on pulmonary vasculature) may worsen V/Q imbalance.
Acute alveolar membrane dysfunction, associated with decreased endothelial nitric oxide synthesis, occurs after CPB and leads to impaired diffusion of less soluble molecules (including O2 and NO)
[19]. Inhomogeneous abnormalities of diffusion capacity to perfusion ratio (DL/Q) generate functional V/Q mismatches
[20]. Within the lung, local regulation of V/Q ratios depends primarily on hypoxic pulmonary vasoconstriction
[21], which occurs by an endothelium dependant mechanism
[22] and so may be deficient after CAB surgery. Inhaled nitric oxide has the capacity to induce vasodilatation throughout the pulmonary vascular tree, including pulmonary micro-vessels (<70 µm)
[23]. However its extremely short half life in contact with high oxygen fractions, blood and endothelial surfaces
[24] suggests it may only persist to reach the better-ventilated respiratory bronchioles and alveoli. Maximal therapeutic pulmonary capillary vasodilatation would then occur adjacent to these better-ventilated respiratory units, especially where alveolar membrane function is preserved. Favored perfusion of these regions minimises intrapulmonary `right to left shunting'.
In this study patients were ventilated with a positive end expiratory pressure of 10 cm H2O (to combat micro atelectasis) and nitric oxide was added to their gas supply. Alveolar recruitment, resulting from the application of PEEP, potentiates iNO induced improvement in arterial oxygenation
[25]. This positive effect of PEEP is observed only when PEEP is associated with alveolar recruitment. When PEEP causes pulmonary over distention the effect of NO inhalation on arterial oxygen tension does not differ in PEEP or zero end expiratory pressure conditions. As a consequence, the positive effect of iNO on arterial oxygenation should be tested after optimization of alveolar recruitment. This means that in our study all patients in the treatment group had alveolar recruitment with PEEP and no PEEP-induced lung over distention.
Our results demonstrating an early improvement in arterial oxygenation, in the absence of changes in pulmonary haemodynamics, are consistent with these considerations. The sustained clinical benefit of nitric oxide therapy, seen in the treatment group, suggests that additional mechanisms may be important. Indeed nitric oxide has proven to be far more than a simple regulator of vascular tone. Particularly nitric oxide exhibits activity within the inflammatory cascade, including a specific antineutrophil effect
[26]. Injured (reperfused) endothelium demonstrates impaired nitric oxide production, associated with neutrophil accumulation and activation
[27]. This process is reversed by nitric oxide donors in experimental models
[28]; potentially aborting secondary inflammatory damage and facilitating a more rapid functional recovery. In the context of this study, medium term pulmonary function, as reflected by mechanical ventilation times, is improved by the addition of iNO to the ventilator circuit. A finding now supported by analogous observations after human lung transplantation
[29].
The sensitivity of this study was limited by the nature of two of the outcome measures. Step-down from ITU and discharge from hospital were only assessed intermittently and these decisions were not subject to a rigorous protocol. This approach reflects our local practice, where patients progress with a consensus being reached between medical and senior nursing staff. Logistic considerations are often a factor. Although potentially blurring differences between the treatment and control groups, these limitations accurately reflect typical cardiac surgical practice, and our study offers a practical assessment of the utility of iNO therapy in this context. Numerically these variables have a skewed distribution and non-parametric methods were applied in our analysis.
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Summary
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Impaired arterial oxygenation after coronary artery bypass surgery may be ameliorated by inhaled nitric oxide, within a dose range of 10–30 ppm. In this small study, we have demonstrated statistically significant early (4-h) improvements in oxygenation with iNO therapy. This benefit is sustained with significant later (24-h) reductions in oxygen requirement and decreased ventilation times in the treatment group. From a practical point of view, we feel that nitric oxide therapy should be considered for patients with poor oxygenation after CAB surgery. Our physiological understanding suggests that a wider group of patients who develop hypoxaemia after other open heart surgical procedures, may also benefit from inhaled nitric oxide treatment. Larger trials are necessary to establish such a benefit in this less homogeneous group of patients.
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Acknowledgments
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We are grateful to Chest Heart and Stroke (Scotland) for their financial support of this study. This study was funded by a grant from Chest Heart and Stroke, Scotland.
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Footnotes
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Presented at the 11th Annual Meeting of the European Association for Cardio-thoracic Surgery, Copenhagen, Denmark, September 28 – October 1, 1997. 
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Abstract
Introduction
