Secondary Logo

Journal Logo

Cardiovascular Anesthesia: Research Report

The Effects of Intravenous Almitrine on Oxygenation and Hemodynamics During One-Lung Ventilation

Moutafis, Marc, MD; Dalibon, Nicolas, MD; Liu, Ngai, MD; Kuhlman, Guy, MD; Fischler, Marc, MD

Author Information
doi: 10.1097/00000539-200204000-00010
  • Free

Abstract

One-lung ventilation (OLV) induces an increase in pulmonary shunt and consequently a decrease in Pao2. Despite ventilation with 100% oxygen, 6%(1) to 11%(2) of patients, in a lateral decubitus position, are required to discontinue OLV because of a pulse oximetric saturation <85 (1) or 90%(2). Routine and effective treatment of hypoxemia in these patients is based on a ventilatory strategy. Capan et al. (3) have demonstrated that the best way to improve Pao2 during OLV is to apply continuous positive airway pressure to the nonventilated lung with or without applying positive end-expiratory pressure to the ventilated lung. However, this may be ineffective (markedly asymmetric lung perfusion with the operative lung being the most perfused, or impaired hypoxic pulmonary vasoconstriction) or inapplicable, for instance during minimally invasive surgical procedures (thoracoscopy, video-assisted thoracic surgery) that require a well-collapsed lung.

The concept of a pharmacologic control of pulmonary blood flow during OLV has gained popularity (4). Several promising methods have been proposed: regional nebulization of nitric oxide (NO) or of prostaglandin E1 (PGE1) (vasodilatation of the ventilated lung), regional perfusion of PGF, and regional nebulization of NG-nitro-l-arginine-methyl-ester or IV almitrine administration (vasoconstriction of the nonventilated lung). Only nebulization of NO has been extensively studied in humans, with mostly poor results (5–11) with the exception of one study (12). The combination of almitrine infusion and inhaled NO prevents the decrease in Pao2 during OLV (7) and was evaluated based on the fact that NO reverses the almitrine-induced pulmonary artery vasoconstriction (13) that may increase right ventricular afterload. However, almitrine infusion alone, which has been reported to increase Pao2 during OLV in an experimental dog model (14,15), has never been studied in humans.

The purpose of this randomized prospective study was to demonstrate whether IV infusion of almitrine could prevent a decrease in Pao2 during OLV.

Methods

The double-blinded, randomized study was approved by the Hospital Ethics Committee. Consecutive patients who were scheduled to undergo thoracic surgical procedures requiring OLV (pneumonectomy, lobectomy) were considered for inclusion in the study if they met the requirements of the experimental protocol and gave their written informed consent.

The main inclusion criterion was estimated blood flow to the operated lung ranging between 45% and 55% of total perfusion (radioisotope regional perfusion test performed a few days before surgery). Patients with even moderate echocardiographic evidence of pulmonary artery hypertension and those receiving any vasoactive drug were excluded.

Arterial blood gas analysis without oxygen administration and routine spirometric evaluation were performed preoperatively.

All patients were premedicated with 5 mg IM midazolam. Before the induction of anesthesia, an IV infusion of normal saline was started, and a 20-gauge radial artery catheter was inserted. Routine monitoring was used. Anesthesia was induced with propofol (2 mg/kg), sufentanil (0.2 μg/kg), and atracurium (0.1 mg/kg) IV and maintained with the same drugs. A left-sided double-lumen endobronchial tube (Broncho-Cath; Mallinckrodt Laboratories, Athlone, Ireland) was placed and positioned initially by auscultation. After turning the patient to the lateral decubitus position, the position of double-lumen endobronchial tube was confirmed by fiberoptic bronchoscopy just before the beginning of OLV and, finally, by the surgeon during the procedure. Ventilatory settings (Evita ventilator; Dräger, Lübeck, Germany) were identical during two-lung ventilation (TLV) or OLV: 100% oxygen, 10 mL/kg tidal volume, 12-min ventilatory frequency, inspiratory to expiratory ratio of 1:2. A 7.5F thermodilution, heparin-coated pulmonary artery catheter was inserted into the right internal jugular vein and zeroed in the horizontal plane of the vertebral column in the lateral position.

Blood pressures were measured by using Baxter Uniflow 43260 transducers (Baxter, Irvine, CA) and displayed using an AS3 monitor (Datex, Helsinki, Finland). Cardiac output (CO) was measured intermittently by injection of 10 mL of ice-cold saline (0°–5°C) using the AS3 monitoring computer. All measurements were distributed randomly during the entire respiratory cycle. CO was taken as the mean of three measurements showing close agreement. Arterial and mixed venous blood were measured by using an automated blood gas analyzer.

Patients were randomly assigned to receive via a peripheral arm vein either placebo (0.9% saline) or an 8 μg · kg−1 · min−1 almitrine infusion that began at OLV initiation. The anesthetic team was blinded to the administered infusion, which was prepared outside the operating room.

The following variables were measured during TLV 10 min after positioning in a lateral decubitus position (TLV-lat), and then every 10 min during OLV for a 30-min period (OLV-10, OLV-20, OLV-30): mean arterial blood pressure, heart rate, right atrial pressure, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure, and CO. Arterial and mixed venous blood gas analyses were performed at the same times. Intrapulmonary shunt fraction (Qs/Qt) was calculated by using standard formula.

If Spo2 decreased to <90% during the study, TLV was restored. Surgery began after OLV-30.

All data were expressed as median ± sem. Preoperative data were compared by using the Mann-Whitney U-test. From the initiation of TLV-lat until the end of the observation period (OLV-30), consecutive measurements were compared by using the repeated-measures analysis of variance. Post hoc analyses were performed with a Wilcoxon’s test (intragroup comparison) and a Mann-Whitney U-test (intergroup comparison). Changes were considered significant at the 5% level (P < 0.05).

Results

Sixteen patients were enrolled in this study. No patient was excluded from this study because of a decrease in Spo2 to <90%.

No significant differences were observed between the placebo group (Group P) and the almitrine group (Group A) with respect to age, sex ratio, height, body weight, preoperative arterial blood gases, and spirometric test (Table 1).

Table 1
Table 1:
 Demographic Data

The values for mean arterial blood pressure, heart rate, PAP, central venous pressure, pulmonary capillary wedge pressure, and CO did not differ significantly between groups (Table 2). Compared with the level found during TLV-lat, Pao2 decreased in Group P and in Group A. Differences were found in intragroup and in intergroup comparisons. Pao2 decreased at OLV-10, OLV-20, and OLV-30 in Group P (P < 0.05) and at OLV-20 and OLV-30 in Group A (P < 0.05). Pao2 values were statistically different between groups at OLV-20 and at OLV-30 (P < 0.05). Mean Pao2 was 178 ± 51 mm Hg 30 min after the beginning of OLV inGroup P and 325 ± 47 mm Hg in Group A (P < 0.05) (Table 3, Fig. 1). There was no significant change in Paco2 throughout the study. Qs/Qt increased significantly after the initiation of OLV in both groups but less so in Group A (Fig. 1).

Table 2
Table 2:
 Time Course Changes of Hemodynamics
Table 3
Table 3:
 Time-Course Changes of Blood Gas Analysis
Figure 1
Figure 1:
Arterial oxygen tension (mm Hg) and shunt fraction (Qs/Qt). Group P = placebo group, Group A = almitrine group, 2LV-lat = two-lung ventilation in the lateral decubitus position, OLV = one-lung ventilation.

Discussion

This study shows that 8 μg · kg−1 · min−1 IV almitrine infusion limits the decrease in Pao2 during OLV without causing major systemic or pulmonary hemodynamic side effects.

Almitrine is a peripheral chemoreceptor agonist, which induces pulmonary vasoconstriction in normal subjects at a dose of 16.5 μg · kg−1 · min−1 without significant vascular peripheral effect (16). Enhancement of hypoxic pulmonary vasoconstriction is observed at a dose of 4 μg · kg−1 · min−1 in normal subjects (17) and at 8 μg · kg−1 · min−1 in patients with chronic obstructive pulmonary disease (18).

In the past few years, attention has focused on IV almitrine in the treatment of patients with acute respiratory distress syndrome (ARDS). The almitrine dose is of prime importance: 16 μg · kg−1 · min−1 of almitrine not only increased Pao2/Fio2 ratio but also increased pulmonary vascular index (13), whereas 8.3 μg · kg−1 · min−1 almitrine increased Pao2 without any significant change in hemodynamic variables (19). A dose-response curve of the effect of almitrine was established by Gallart et al. (20) in patients with ARDS and by Sommerer et al. (21) in an animal model of acute lung injury. In the animal model, 0.5 to 2 μg · kg−1 · min−1 almitrine increased Pao2 and decreased intrapulmonary shunt whereas larger doses had no beneficial effect or even worsened shunt (21). The maximal increase in Pao2/Fio2 and decrease in intrapulmonary shunt were observed at almitrine infusion rates of 2 μg · kg−1 · min−1 in patients with septic shock and 4 μg · kg−1 · min−1 in patients without septic shock whereas PAP and pulmonary artery resistance index increased dose-dependently from 2 to 16 μg · kg−1 · min−1(20). The effect of almitrine could be attributed to a diversion of blood flow from nonventilated lung regions toward those with normal ventilation-perfusion relationships (22).

OLV is a quite simple physiopathologic model compared with ARDS, Pao2 reflecting mainly the ratio of perfusion between both lungs. In a lateral decubitus position, the nonventilated nondependent lung has a reduced perfusion because of gravity, physical collapse of the operative lung, and hypoxic pulmonary vasoconstriction. A low nonventilated nondependent lung perfusion is associated with a high Pao2 value, and conversely. Changes in Pao2 evolution during OLV vary widely among patients because of the large number of factors involved, especially those decreasing hypoxic pulmonary vasoconstriction (halogenated anesthetics, acid/base imbalance, temperature changes, surgical trauma, etc.) (23).

The concept of nonventilatory treatment or of pharmacologic manipulation of pulmonary blood flow during OLV is not new since Scherer et al. (24) demonstrated in 1986 that pulmonary artery catheter balloon inflation and PGF infusion were equally effective in improving oxygenation during OLV. Almitrine administration during OLV was studied in anesthetized closed-chest dogs ventilated in one lung with pure oxygen and in the other with either pure oxygen or a hypoxic gas mixture. In this model, Chen et al. (15) reported the dose-response curve of almitrine effect on oxygenation and on the percentage of blood flow of the hypoxic lung. No significant effect was observed between 0.003 and 0.3 μg · kg−1 · min−1 of almitrine, and Pao2 increased and hypoxic lung blood flow decreased at 3 μg · kg−1 · min−1 of almitrine (15). In a similar model, a dose of 2 μg · kg−1 · min−1 almitrine was also effective (14). Conversely, larger doses of almitrine (14.3 μg · kg−1 · min−1) diverted the blood flow from the hyperoxic lung to the hypoxic lung, causing a reduction of the hypoxic pulmonary vasoconstriction response (25).

Using a 8 μg · kg−1 · min−1 dose of almitrine, we report a smaller decrease in Pao2 during OLV than in the Placebo group without any hemodynamic modification. The limited decrease in Pao2 is probably attributable to a redistribution of pulmonary blood flow from the atelectatic to the ventilated lung. A similar situation in which pulmonary blood flow from shunt areas is redistributed to lung units with normal ventilation-perfusion ratios has been reported both in ARDS patients and in an experimental model (22), using the multiple inert gas elimination technique. We did not observe any changes in PAP or CO that would be consistent with the pulmonary vasoconstriction effect of almitrine (20). This finding can be explained by the choice of an intermediate dose of almitrine and by the inclusion of patients with a high pulmonary vascular capacitance.

In conclusion, 8 μg · kg−1 · min−1 almitrine should prevent and limit the OLV-induced decrease in Pao2 without causing any hemodynamic changes in patients without pulmonary hypertension undergoing OLV.

References

1. Slinger P, Suissa S, Triolet W. Predicting arterial oxygenation during one-lung anaesthesia. Can J Anaesth 1992; 39: 1030–5.
2. Watanabe S, Noguchi E, Yamada S, et al. Sequential changes of arterial oxygen tension in the supine position during one-lung ventilation. Anesth Analg 2000; 90: 28–34.
3. Capan LM, Turndorf H, Patel C, et al. Optimization of arterial oxygenation during one-lung anesthesia. Anesth Analg 1980; 59: 847–51.
4. Hedenstierna G, Reber A. Manipulating pulmonary blood flow during one-lung anaesthesia. Acta Anaesthesiol Scand 1996; 40: 2–4.
5. Rich GF, Lowson SM, Johns RA, et al. Inhaled nitric oxide selectively decreases pulmonary vascular resistance without impairing oxygenation during one-lung ventilation in patients undergoing cardiac surgery. Anesthesiology 1994; 80: 57–62.
6. Freden F, Wei SZ, Berglund JE, et al. Nitric oxide modulation of pulmonary blood flow distribution in lobar hypoxia. Anesthesiology 1995; 82: 1216–25.
7. Moutafis M, Liu N, Dalibon N, et al. The effects of inhaled nitric oxide and its combination with intravenous almitrine on Pa o2 during one-lung ventilation in patients undergoing thoracoscopic procedures. Anesth Analg 1997; 85: 1130–5.
8. Wilson WC, Kapelanski DP, Benumof JL, et al. Inhaled nitric oxide (40 ppm) during one-lung ventilation, in the lateral decubitus position, does not decrease pulmonary vascular resistance or improve oxygenation in normal patients. J Cardiothorac Vasc Anesth 1997; 11: 172–6.
9. Hambraeus-Jonzon K, Bindslev L, Frostell C, Hedenstierna G. Individual lung blood flow during unilateral hypoxia: effects of inhaled nitric oxide. Eur Respir J 1998; 11: 565–70.
10. Freden F, Berglund JE, Hedenstierna G. Pulmonary blood flow distribution in lobar hypoxia: influence of cardiac output and nitric oxide inhalation. Scand Cardiovasc J 1999; 33: 215–21.
11. Fradj K, Samain E, Delefosse D, et al. Placebo-controlled study of inhaled nitric oxide to treat hypoxaemia during one-lung ventilation. Br J Anaesth 1999; 82: 208–12.
12. del Barrio E, Varela G, Sastre JA, et al. La administracion inhalatoria de oxido nitrico durante la ventilacion pulmonar selectiva disminuye el shunt intrapulmonar. Rev Esp Anestesiol Reanim 1999; 46: 247–51.
13. Lu Q, Mourgeon E, Law-Koune JD, et al. Dose-response curves of inhaled nitric oxide with and without intravenous almitrine in nitric oxide-responding patients with acute respiratory distress syndrome. Anesthesiology 1995; 83: 929–43.
14. Takasaki M, Oh-Oka T, Saito Y, Kosaka Y. Low dose almitrine bismesylate improves pulmonary gas exchange during canine one-lung hypoxia. Crit Care Med 1989; 17: 661–5.
15. Chen L, Miller FL, Clarke WR, et al. Low-dose almitrine bismesylate enhances hypoxic pulmonary vasoconstriction in closed-chest dogs. Anesth Analg 1990; 71: 475–83.
16. Gluskowski J, Gorecka D, Hawrylkiewicz I, Zielinski J. Acute effects of almitrine infusion on pulmonary haemodynamics in normal man. Bull Eur Physiopathol Respir 1984; 20: 313–7.
17. Melot C, Dechamps P, Hallemans R, et al. Enhancement of hypoxic pulmonary vasoconstriction by low dose almitrine bismesylate in normal humans. Am Rev Respir Dis 1989; 139: 111–9.
18. Saadjian AY, Philip-Joel FF, Barret A, et al. Effect of almitrine bismesylate on pulmonary vasoreactivity to hypoxia in chronic obstructive pulmonary disease. Eur Respir J 1994; 7: 862–8.
19. Prost JF, Desche P, Jardin F, Margairaz A. Comparison of the effects of intravenous almitrine and positive end-expiratory pressure on pulmonary gas exchange in adult respiratory distress syndrome. Eur Respir J 1991; 4: 683–7.
20. Gallart L, Lu Q, Puybasset L, et al. Intravenous almitrine combined with inhaled nitric oxide for acute respiratory distress syndrome. The NO Almitrine Study Group. Am J Respir Crit Care Med 1998; 158: 1770–7.
21. Sommerer A, Kaisers U, Dembinski R, et al. Dose-dependent effects of almitrine on hemodynamics and gas exchange in an animal model of acute lung injury. Intensive Care Med 2000; 26: 434–41.
22. Dembinski R, Max M, Lopez F, et al. Effect of inhaled nitric oxide in combination with almitrine on ventilation-perfusion distributions in experimental lung injury. Intensive Care Med 2000; 26: 221–8.
23. Benumof JL. Isoflurane anesthesia and arterial oxygenation during one-lung ventilation. Anesthesiology 1986; 64: 419–22.
24. Scherer R, Vigfusson G, Lawin P. Pulmonary blood flow reduction by prostaglandin F2 alpha and pulmonary artery balloon manipulation during one-lung ventilation in dogs. Acta Anaesthesiol Scand 1986; 30: 2–6.
25. Chen L, Miller FL, Malmkvist G, et al. High-dose almitrine bismesylate inhibits hypoxic pulmonary vasoconstriction in closed-chest dogs. Anesthesiology 1987; 67: 534–42.

Attention Authors!

Submit Your Papers Online

You can now have your paper processed and reviewed faster by sending it to us through our new, web-based Rapid Review System. Submitting your manuscript online will mean that the time and expense of sending papers through the mail can be eliminated. Moreover, because our reviewers will also be working online, the entire review process will be significantly faster. You can submit manuscripts electronically via http://www.rapidreview.com. There are links to this site from the Anesthesia & Analgesia website (http://www.anesthesia-analgesia.org), and the IARS website (http://www.iars.org). To find out more about Rapid Review, go to http://www.rapidreview.com and click on “About Rapid Review.”

© 2002 International Anesthesia Research Society