Low- vs high-dose almitrine combined with nitric oxide to prevent hypoxia during open-chest one-lung ventilation

T. Silva-Costa-Gomes1, L. Gallart1,*, J. Vallès1, L. Trillo1, J. Minguella2 and M. M. Puig1

1 Department of Anesthesiology and 2 Department of Surgery, Hospital Universitari del Mar, Institut Municipal d'Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain

* Corresponding author: Department of Anesthesiology, Hospital Universitari del Mar, Passeig Maritim 25, 08003 Barcelona, Spain. E-mail: LGallart{at}imas.imim.es

Accepted for publication May 16, 2005.


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Almitrine combined with inhaled nitric oxide (NO) can prevent hypoxia during one-lung ventilation (OLV). The optimal dose of almitrine that would provide therapeutic advantage with few side-effects during open-chest OLV has not been established.

Methods. Forty-two patients undergoing thoracotomy were randomly allocated to three groups: placebo, almitrine 4 µg kg–1 min–1 and inhaled NO 10 p.p.m. (ALM4+NO), and almitrine 16 µg kg–1 min–1 and inhaled NO 10 p.p.m. (ALM16+NO). Gas exchange, haemodynamic and respiratory variables and plasma concentrations of almitrine and lactate were monitored. Measurements were obtained with the patient awake (baseline), after induction of anaesthesia with two-lung ventilation (control 2LV), 20 min after treatment (2LV+T), and then at 10, 20 and 30 min of OLV (OLV10', OLV20' and OLV30') with 1.

Results. In the placebo group, OLV impaired and increased pulmonary shunt [16 (SD 7) kPa and 42 (10)% respectively]. These improved with ALM4+NO [26 (10) kPa and 31 (7)%; P<0.001]. ALM16+NO further improved to 36 (13) kPa (P<0.0001) but gave no improvement in the shunt. Mean pulmonary artery pressure was similar in the placebo and ALM4+NO groups [20 (4) vs 23 (5) mm Hg], whereas it was increased in the ALM16+NO group to 28 (8) mm Hg (P<0.01). Plasma concentrations of almitrine and lactate were unaltered by the treatments.

Conclusions. Low-dose almitrine (4 µg kg–1 min–1) together with inhaled NO significantly improves oxygenation during open-chest OLV, without modifying pulmonary haemodynamics. An increased dose of almitrine (16 µg kg–1 min–1) with inhaled NO further improves arterial oxygenation, but also increases mean pulmonary artery pressure.

Keywords: almitrine ; complications, hypoxia ; nitric oxide ; surgery, thoracic


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Hypoxia associated with lung collapse is the main problem related to one-lung ventilation (OLV) during open-chest thoracic surgery. To correct it, the most widely used strategy is the administration of continuous positive airway pressure (CPAP) to the non-dependent lung. However, CPAP can fail to improve oxygenation in approximately 5% of patients,1 can impede the lung collapse required to minimize lung trauma and facilitate surgery,2 and sometimes cannot be administered for technical reasons. When hypoxia is refractory to optimal ventilation and CPAP cannot be the solution, alternative methods are needed.

Intravenous almitrine combined with inhaled nitric oxide (iNO) improves hypoxia in patients with acute respiratory distress syndrome (ARDS).35 Almitrine enhances hypoxic pulmonary vasoconstriction (HPV) in non-ventilated lung units, while iNO dilates pulmonary vessels from the ventilated areas. Regarding OLV, only one group of investigators demonstrated that almitrine alone or combined with iNO improved hypoxia,68 but the optimal dose of almitrine, combined with iNO during open-chest OLV, that would provide improvement in oxygenation with minimal side-effects is unknown. The present investigation was designed to address this issue. A preliminary account of the results has been given in a published abstract.9


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This prospective, randomized, double-blind, placebo-controlled trial was approved by the ethics committee of our hospital (CEIC-IMAS) and by the Ministerio de Sanidad y Consumo, Spain. All the patients signed informed consent before entering the study, and were protected by a liability insurance.

Forty-two consecutive patients, aged 18–70 yr and undergoing open-chest thoracotomy for lung surgery, entered the study. Exclusion criteria were previous thoracic surgery, liver or kidney dysfunction, left ventricular failure or arrhythmias, fever, sepsis or haemodynamic instability, polyneuropathy, pregnancy and known allergy to any of the drugs used in the study. All the patients received ranitidine 150 mg and diazepam 10 mg by mouth the night before and again 2 h before surgery.

On arrival in the operating room, a thoracic epidural catheter (T4–T7) was inserted with the patient in sitting position, and a test dose (bupivacaine 0.5% 3 ml plus epinephrine 1:200 000) administered in order to exclude an intravascular or intrathecal position of the catheter. No more epidural local anaesthetics were used during the study in order to avoid effects on HPV.10 11 Afterwards, a radial artery cannula and a pulmonary artery catheter (through the subclavian vein) were inserted.

Once the monitoring was established, and after a 5 min resting period, baseline haemodynamic and respiratory variables were recorded. Then general anaesthesia was induced and the study protocol started. During the protocol, the following were monitored in all patients: haemoglobin oxygen saturation using pulse oximetry (); five-lead ECG with automatic S-T analysis and arrhythmia recording, invasive arterial blood pressure, pulmonary artery pressure, central venous pressure, pulmonary capillary wedge pressure, cardiac output using a thermal dilution technique (Tramscope; Marquette Electronics, WI, USA), capnography, inspired and expired oxygen concentrations, tidal volume and airway pressure (Capnomac Ultima; Datex-Ohmeda, Helsinki, Finland). The variables were displayed on a screen and recorded with a data acquisition system (Acknowledge and MP100; Biopac, Santa Barbara, CA, USA) for further off-line analysis.

Anaesthesia was induced with propofol 1 mg kg–1, atracurium 0.5 mg kg–1 and remifentanil 0.5 µg kg–1 min–1 (until the endobronchial tube was inserted), and was maintained with propofol (3 mg kg–1 h–1), atracurium (0.4 mg kg–1 h–1), and titrated doses of remifentanil to achieve an adequate depth of anaesthesia. The infusion of remifentanil was increased or decreased in order to maintain mean arterial pressure and heart rate within a 20% range of the preoperative values, and the value of bispectral index (BIS®; Aspect Medical Systems, Newton, MA, USA) between 40 and 60. Bronchial intubation was performed using a Robertshaw double-lumen tube, and its correct position assessed by fibre-optic bronchoscopy. No clamping of the tubes was used to check the positioning because repeated intermittent cycles of deflation–inflation could potentiate HPV.12 The lungs were mechanically ventilated (Elsa ventilator; Engström, Stockholm, Sweden) with an of 1, without rebreathing, using inspiratory flow up to 60 litre min–1, tidal volume 6 ml kg–1, respiratory rate 10–16 b.p.m., inspiratory pause as provided automatically by the ventilator and an I:E ratio of 1:2. Ventilatory settings were adjusted to achieve between 4.0 and 5.3 kPa. The maximal plateau pressure was limited to 30 cm H2O to avoid barotrauma;13 if the pressure increased over this value, the tidal volume was reduced, permitting hypercapnia. Ventilatory settings were not modified during the study in order to evaluate the effects of the treatment on .

Using a random number table, a number was assigned to every patient in a closed envelope; the patients were thus allocated randomly to the three treatment groups: (i) placebo group, i.v. saline infusion; (ii) ALM4+NO group, almitrine 4 µg kg–1 min–1 by continuous i.v. infusion plus iNO 10 p.p.m.; (iii) ALM16+NO group, almitrine 16 µg kg–1 min–1 by continuous i.v. infusion plus iNO 10 p.p.m.

Almitrine bismesylate (Vectarion®; Servier, Neuilly-sur-Seine, France) and nitric oxide (Air Liquide, Paris, France) were prepared and administered by an investigator who was not involved in taking the measurements or running the study. Nitric oxide was stored in bottles containing 450 p.p.m. and delivered in the inspiratory limb of the ventilator14 with a sequential mode delivery system (Opti-NO, Taema, (Air Liquide), Antony, France). This system produces a characteristic sound, which is synchronous with inspiration. To guarantee the blind administration of NO, Opti-NO was always connected and a three-way stopcock was used. It was turned to the patient in groups receiving NO and to the gas evacuation system in the placebo group. The concentration of iNO delivered was monitored at the inspiratory limb, next to the patient, with a fast-response chemiluminescence device (NOX EVA 2000; Air Liquide).

The measurements were taken and variables recorded at the following time intervals:

Baseline. Patient awake and supine, breathing spontaneously, 0.21.
Control 2LV. Patient anaesthetized, in lateral decubitus position, two-lung ventilation, closed chest and 1. After this measurement the treatment was started according to the group assigned, and continued until the end of the study.
2LV+T. Measurements obtained 20 min after the treatment without modifying any of the previous settings. Then OLV was started and the pleural cavity immediately opened. The surgeon continued with the surgical procedure without ligation of pulmonary vessels.
OLV10'. Ten minutes after OLV in lateral decubitus.
OLV20'. Twenty minutes after OLV in lateral decubitus.
OLV30'. Thirty minutes after OLV in lateral decubitus.

Blood samples for almitrine determination (HPLC/UV; Biotec Centre, Orléans, France) were obtained at baseline, 2LV+T and OLV30' time intervals. Haemoglobin and lactate concentrations were assessed at the start (baseline) and end (OLV30') of study. Lactate was determined with a specific electrode (Radiometer; Copenhagen, Denmark). Plasma samples taken at different time intervals were stored for future measurements.

The adequacy of lung collapse was evaluated by the surgeon, and classified as excellent, good (could be improved), deficient or failure to collapse. Patients with values of below 90% were connected to a CPAP system, which was considered a rescue treatment for hypoxia. The intraoperative exclusion criteria were: (i) haemodynamic instability leading to the administration of vasopressors or vasodilators; (ii) need to modify the position of the bronchial tube or to perform inflating/deflating manoeuvres of the cuff; (iii) lung collapse, classified as deficient or failure to collapse; and (iv) bleeding that caused an intraoperative decrease in haemoglobin concentration of >2.5 g dl–1. The length of hospital admission was obtained from the hospital's database.

The sample size and power analysis were calculated from preliminary data,9 using specific software (Granmo 5.2 WIN; Institut Municipal d'Investigacions Mèdiques, Barcelona, Spain). It was established that groups of 14 patients could determine a 50% difference in among treatment groups ({alpha}=0.05, ß=0.1). Normal distributions of continuous variables were assessed with the Kolmogorov–Smirnov test. If normality was not observed, a non-parametric test was applied.

Demographic, respiratory and haemodynamic characteristics of the three groups of patients were compared using one-way analysis of variance (ANOVA) or the Kruskal–Wallis test. To analyse differences in the final values of the variables, analysis of covariance was performed with group treatment as fixed factor and before-treatment (2LV) variables as covariates. Post hoc tests were performed using the Tukey–Kramer method. To evaluate if the treatment decreased the number of patients who needed to be rescued with CPAP, the {chi}2-test was used. To evaluate possible changes in almitrine plasma concentrations (2LV+T vs OLV30') and lactate (baseline vs OLV30'), Student's t-test for paired data was used. ANOVA was used to evaluate differences in duration of hospital stay. A P-value <0.05 was considered statistically significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Forty-seven patients met the inclusion criteria for the study. Of these, four were excluded because of inadequate lung collapse or technical problems with the double-lumen tube and one because of technical problems with the pulmonary artery catheter. No patients were excluded because of haemodynamic instability or excessive bleeding. Thus, 42 patients (14 per group) entered the study.

Normal distribution of the variables was confirmed. Demographic characteristics of the patients are shown in Table 1 and baseline respiratory and haemodynamic variables are shown in Tables 2 and 3. There were no differences in any of these variables between the groups. Also, these variables did not differ between groups at 2LV (two-lung mechanical ventilation, before starting the treatment).


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Table 1 Patient characteristics and type of surgery. Mean (range) or mean (SD). FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; DLCO, carbon monoxide diffusion

 

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Table 2 Effects of the treatment on the respiratory variables. All values are mean (SD). 2LV, two-lung ventilation; 2LV+T, two-lung ventilation together with treatment; OLV10', OLV20', OLV30': 10, 20 and 30 min after onset of one-lung ventilation; ALM4+NO, almitrine 4 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m; ALM16+NO, almitrine 16 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m.; , haemoglobin oxygen saturation measured by pulse oximetry; QS/QT, pulmonary shunt. Covariance analysis and Tukey–Kramer as post hoc test at OLV30'.

 

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Table 3 Effects of treatment on haemodynamic parameters. All values are mean (SD). 2LV, two-lung ventilation; 2LV+T, two-lung ventilation together with treatment; OLV10', OLV20', OLV30': 10, 20 and 30 min after onset of one-lung ventilation; ALM4+NO, almitrine 4 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m.; ALM16+NO, almitrine 16 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m. HR, heart rate; MAP, mean arterial pressure; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; CVP, central venous pressure; CI, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance. Covariance analysis and Tukey–Kramer as post hoc test at OLV30'.

 
As shown in Table 2 and Fig. 1, OLV impaired in the placebo group. Arterial oxygenation was better in the ALM4+NO group and further improved in the ALM16+ NO group (P<0.0001). Venous admixture was lower in patients treated with almitrine+iNO (P<0.001), without significant differences between the two doses of almitrine (Table 2, Fig. 2).



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Fig 1 Effects of the treatment on . 2LV, two-lung ventilation; 2LV+T, two-lung ventilation together with treatment; OLV10', OLV20', OLV30', 10, 20 and 30 min after the onset of one-lung ventilation; ALM4+ NO, almitrine 4 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m.; ALM16+NO, almitrine 16 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m. ***All groups different (P<0.001).

 


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Fig 2 Effects of the treatment on pulmonary shunt (QS/QT). 2LV, two-lung ventilation; 2LV+T, two-lung ventilation together with treatment; OLV10', OLV20', OLV30', 10, 20 and 30 min after onset of one-lung ventilation; ALM4+NO, almitrine 4 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m.; ALM16+NO, almitrine 16 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m. **Treatment groups significantly different from placebo (P<0.01).

 
Two patients in the placebo group had lower than 90% during OLV and needed to be rescued with CPAP; none of the patients who received treatment had to be rescued. Treatment with ALM16+NO increased mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance when compared with placebo. These effects on mPAP were not observed in the ALM4+NO group (Table 3, Figs 3 and 4).



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Fig 3 Effects of the treatment on mean pulmonary artery pressure (mPAP). 2LV, two-lung ventilation; 2LV+T, two-lung ventilation + treatment; OLV10', OLV20', OLV30', controls at 10, 20 and 30 min of OLV; ALM4+NO, almitrine 4 µg kg–1 min–1 + inhaled NO 10 p.p.m.; ALM16+ NO, almitrine 16 µg kg–1 min–1 + inhaled NO 10 p.p.m. *ALM16+NO differs from others (P<0.05).

 


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Fig 4 Effects of the treatment on pulmonary vascular resistance (PVR). 2LV, two-lung ventilation; 2LV+T, two-lung ventilation together with treatment; OLV10', OLV20', OLV30', 10, 20 and 30 min after onset of one-lung ventilation; ALM4+NO, almitrine 4 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m.; ALM16+NO, almitrine 16 µg kg–1 min–1 combined with inhaled nitric oxide 10 p.p.m. *ALM16+NO differs from placebo (P<0.05).

 
Heart rate and cardiac index were slightly increased in the ALM16+NO group at OLV30' (Table 3). No significant differences in these variables were observed between the placebo and ALM4+NO groups. The remaining haemodynamic parameters were not different among groups.

Plasma concentrations of almitrine remained unaltered during the study, without significant differences between the time intervals 2LV+T and OLV30'. These concentrations were [mean (SD)] 157 (73) and 175 (52) ng ml–1 at 2LV+T and OLV30' respectively in the ALM4+NO group, and 659 (113) and 599 (183) ng ml–1 in the ALM16+NO group. Plasma lactate concentrations remained within the normal range in all patients (0.5–1.6 mmol litre–1), and were unchanged between the baseline and OLV30'.

No differences among groups were observed in the hospital outcome of the patients. Length of hospital stay was 15 (10), 17 (11) and 12 (3) days for the placebo, ALM4+NO and ALM16+NO groups respectively, and intrahospital mortality was 0/14, 1/14 and 0/14 respectively. No clinical signs of polyneuropathy were observed in any patient at the time of discharge.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study showed that almitrine combined with iNO reduced the hypoxia associated with the collapse of the lung during open-chest OLV. This effect was dose-related because the high dose of almitrine (16 µg kg–1 min–1) increased more strikingly than the lower dose (4 µg kg–1 min–1). Low-dose almitrine+iNO had no significant effect on pulmonary haemodynamics, while high-dose almitrine+iNO increased mPAP. Our study also showed that, after preloading for 20 min, a continuous infusion of almitrine provides a steady plasma concentration of the drug.

So far, only one group of investigators has reported that almitrine and iNO can improve hypoxia during OLV,68 but they made several assumptions. First, they assumed that their results obtained using high-dose almitrine during closed-chest OLV6 7 could be applied to open-chest ventilation. However, the situations are not identical. Lung collapse, respiratory mechanics and pulmonary circulation are different in both conditions. Secondly, they assumed8 that low-dose almitrine would be as effective as high-dose, as seen in acute respiratory distress syndrome (ARDS).15 But there is conflicting information on this issue.4 1622 Our results show that the improvement in oxygenation can be dose-dependent. Finally, these authors assumed6 7 lack of pulmonary hypertension with high-dose almitrine and iNO. In our study almitrine caused a dose-dependent increase in mPAP that could have been attenuated, but not abolished, by iNO.4

In our study, we observed a marked dose-dependent increase in but we could not demonstrate the same pattern in venous admixture. This is probably because the shunt is a calculated parameter, and because patients receiving almitrine had close to 100%, without differences between doses. Other investigators using almitrine and iNO also found an improvement in without a decrease in pulmonary shunt.5 Rescue with CPAP was necessary in two patients in the placebo group and none of treatment groups, without differences between groups. Given the very low frequency of rescue, the power to make statistical comparisons is low.

The slight increases in heart rate and cardiac index observed in the ALM16+NO group have also been observed in patients with ARDS.3 4 On the other hand, the effects on pulmonary vascular resistance were not parallel to those observed in mPAP, probably because this is a calculated parameter. Concerning iNO, the optimal concentration of iNO for OLV, alone or combined with almitrine, has not been established.2326 We decided to use 10 p.p.m.27 because this is the maximal dose that can be safely given without increasing methaemoglobinaemia and higher oxides of nitrogen.28

We assumed, like others,7 that iNO would increase the therapeutic effects of almitrine during OLV, mainly because iNO is more effective in the presence of pulmonary vasoconstriction.29 However, as the effectiveness of iNO is uncertain25 3032 further studies are needed to compare the administration of almitrine alone or combined with iNO, in order to clarify the real influence of iNO on the effects of almitrine.

In the design of the study, we tried to be as close as possible to the usual clinical situation, i.e. the chest open, ongoing surgery and total i.v. anaesthesia, in order to avoid effects of the inhaled anaesthetics on HPV. Thus, the interaction of these drugs with almitrine is unknown. Regarding epidural anaesthesia, although it could modify HPV,10 11 we used it because it has become a standard of care in these patients.33

Lactate concentrations were unaltered during the study. An increase in this parameter has been reported,34 but only in patients with shock and previous liver dysfunction. These were exclusion criteria in our study. The plasma concentrations of almitrine also remained unmodified in both groups throughout the study. These results show that the method used to administer almitrine was adequate to ensure homogeneous plasma concentrations, and it is consistent with data previously reported about the pharmacokinetics of almitrine.35

No clinical signs of peripheral neuropathy were observed in any patient at the time of hospital discharge. Polyneuropathy is a side-effect related to almitrine, but it has been observed in patients receiving high doses over periods of several months3638 and the effects are reversed after stopping the treatment.39 The hospital stay and intrahospital mortality of the patients was similar in all groups. It would probably be difficult to demonstrate an eventual improvement in the outcome related to the treatment, mainly because of the sample size needed. This study is at odds with a recently published editorial that has criticized the role of vasoactive substances in modifying HPV during OLV.40 The effects of almitrine on HPV have been described extensively16 41 42 and have been accepted as a rationale for improving oxygenation when given with iNO.4 68 43 Regarding the ethics of its use, we do not propose this treatment as a standard choice. CPAP is an easy and effective method to improve hypoxia. Almitrine and iNO are effective, but these may not be readily available and have risks of toxicity, although the risks are minimized during short low-dose treatments. Thus, these might be considered as an alternative treatment for hypoxia when CPAP fails and/or is not suitable to be used and OLV must be continued.

In conclusion, our study has shown that almitrine at a low dose (4 µg kg–1 min–1) combined with 10 p.p.m. of inhaled nitric oxide clearly improves hypoxia related to open-chest, one-lung ventilation. A higher dose of almitrine (16 µg kg–1 min–1), also with iNO, further improves arterial oxygenation, but a significant increase in pulmonary artery pressure is also observed. This treatment can be an effective alternative when standard methods, such as CPAP, fail to improve hypoxia.


    Acknowledgments
 
Supported by a grant from FIS 98/1049, Ministerio de Sanidad y Consumo, Spain. The authors thank Drs Joan Vila and Olga Pol for their support in reviewing the statistics.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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