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Anesth Analg 2004;98:590-594 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000099715.40831.2A
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Abstract |
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We performed this prospective randomized double-blinded study to assess the ability of almitrine to treat hypoxemia during one-lung ventilation (OLV). Twenty-eight patients were anesthetized with propofol, sufentanil, and atracurium; lung separation was achieved with a double-lumen tube. A transesophageal Doppler probe was inserted to evaluate cardiac index. If SpO2 was equal to or decreased to <95% during OLV (inspired fraction of oxygen of 0.6), patients were included in the study and received a placebo or almit- rine (12 µg · kg-1 · min-1 for 10 min followed by 4 µg · kg-1 · min-1) infusion until SpO2 reached 90% or decreased to <90% (exclusion from the study). Eighteen of the 28 patients were included and received either almitrine (n = 9) or a placebo (n = 9). Treatment was discontinued in 1 patient in the almitrine group and 6 in the placebo group (P < 0.05). Treatment was successful (SpO2 remaining
95% during OLV) in 8 patients in the almitrine group and 1 in the placebo group (P < 0.01). Heart rate, arterial blood pressure, and cardiac index did not change throughout the study, but we could obtain an adequate aortic blood flow signal in only half of the patients. Almitrine could be used to treat hypoxemia during OLV. IMPLICATIONS: IV almitrine improves oxygenation during one-lung ventilation without hemodynamic modification. Such treatment could be used when conventional ventilatory strategy fails to treat hypoxemia or cannot be used.
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Introduction |
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Lung isolation techniques are used especially for lung surgery but are also used in esophageal, vascular, and other nonpulmonary surgical procedures in the operative period. This technique has an important drawback because one-lung ventilation (OLV) induces an increase in pulmonary shunt and consequently a decrease in PaO2. Despite ventilation with 100% oxygen, for 6% (1) to 11% (2) of patients operated in a lateral decubitus position, it is necessary to discontinue OLV because of pulse oximetric saturation <85% (1) or <90% (2), respectively. In the supine position, severe hypoxemia occurs in the majority of patients after starting OLV (2). Routine and effective treatment of hypoxemia in these patients is based on a ventilatory strategy: especially continuous positive airway pressure to the nonventilated lung with or without applying positive end-expiratory pressure to the ventilated lung (3). However, the concept of pharmacological control of pulmonary blood flow during OLV has gained popularity with several promising methods: regional nebulization of nitric oxide (NO) or of prostaglandin (PG) E1 (vasodilation of the ventilated lung), regional perfusion of PGF-2
, and regional nebulization of NG-nitro-L-arginine-methyl-ester or IV almitrine administration (vasoconstriction of the nonventilated lung) (4). Only nebulization of NO has been extensively studied in humans, with generally poor results. Two studies have shown that infusion of almitrine alone (5) or associated with nebulization of NO (6) prevents an OLV-induced decrease in PaO2. Except in one case report (7), almitrine has never been reported to treat hypoxemia during OLV in humans. The purpose of this randomized prospective study was to demonstrate whether almitrine could be effective in such a situation. |
Methods |
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This 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 study population was selected on the following criteria: 1) age between 18 and 70 yr; 2) ASA physical status I–III; 3) estimated blood flow to the nonventilated lung ranging between 45% and 55% of total perfusion (a radioisotope regional perfusion test was performed a few days before surgery); 4) pulmonary artery systolic pressure <40 mm Hg (echocardiographic measurement); 5) no history or sign of ischemic heart disease; 6) normal liver function; and 7) no preoperative treatment with any vasoactive drug.
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 and connected to a transducer and was displayed using an AS/3 monitor. Routine monitoring was used. After breathing oxygen, anesthesia was induced with propofol (2 mg/kg), sufentanil (0.2 µg/kg), and atracurium (0.5 mg/kg) IV and maintained with the same drugs to obtain a bispectral index between 40 and 50. 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 the double-lumen endobronchial tube was confirmed by fiberoptic bronchoscopy just before the beginning of OLV and by the surgeon during the procedure. Ventilatory settings (Evita ventilator; Dräger, Lübeck, Germany) were identical during two-lung ventilation or OLV: mixture of oxygen and air (FIO2 0.6), 8 mL/kg tidal volume, 12-min ventilatory frequency, and inspiratory to expiratory ratio of 1:2.
A transesophageal Doppler probe connected to a monitor (Cardio-Q, Gamida, France) was advanced gently until its tip was located in the mid-esophagus, approximately 35 cm from the incisors, and then rotated so that the transducer faced posteriorly and a characteristic aortic blood flow signal was obtained. Before each measurement, the esophageal probe position was verified to ensure optimal acquisition of the maximal velocity signal. The gain setting was adjusted to obtain the best outline of the aortic velocity waveform and a 300-Hz high-pass filter eliminated the noise related to low-frequency vessel wall motion. Aortic flow was measured by Doppler. The monitor calculated cardiac output using a nomogram based on the patient’s age, weight, and height to obtain a cross-sectional area of the descending thoracic aorta. A correcting factor (1.43) was applied to transform the blood flow measured in the descending thoracic aorta into global cardiac output, assuming that a constant fraction (70%) of the total blood flow passes through the descending aorta (8).
OLV was begun when the surgeon opened the pleural cavity. If pulse oximetric saturation (SpO2) was equal to or decreased to <95%, patients were randomly assigned using a random-number table to a placebo or almitrine group and received via a peripheral arm vein an infusion previously prepared outside the operating room. In the almitrine group (group A), patients received 12 µg · kg-1 · min-1 almitrine infusion for 10 min followed by 4 µg · kg1 · min-1 almitrine until the surgeon clamped one of the nonventilated lung or lobe vessels. In the placebo group (group P), patients received the same volume of 0.9% saline. The anesthetic team was blinded as to the administered infusion.
Treatment was continued as long as SpO2 was more than 90%. If SpO2 reached 90% or decreased to <90%, the patient was excluded from the study, FIO2 was increased to 1.0 and, if necessary, continuous oxygen positive airway pressure was applied to the nonventilated lung.
If the cardiac index (CI) decreased during placebo or almitrine infusion by more than 20% from the value measured at T0, the infusion was stopped and the case considered as a failure. In this case, the anesthesiologist in charge of the patient was informed of the nature of the infused drug, allowing the choice of a treatment (volume loading, NO, or vasoconstrictor).
SpO2 was continuously recorded. The following variables were measured: a) time when SpO2 decreased to <95% (T0), b) time at the end of the initial loading dose of almitrine or saline (T1), c) time just before surgical occlusion of blood flow to the nonventilated lung or lobe took place (T2). They consisted of heart rate, mean arterial blood pressure, CI determined by transesophageal Doppler, and arterial blood gases.
Treatment was considered as a success when SpO2 remained equal or more than 95% throughout the study.
We postulated that almitrine treatment would be effective to treat hypoxemia in 80% of the patients and that placebo would be effective in 20% of the patients. A sample size of 6 patients per group gives 80% power at the 5% significance level. Finally, we decided to recruit 9 patients per group. As the data were not normally distributed because of the small sample size, Fisher’s exact test was used to compare qualitative variables and the Mann-Whitney U-test was used to compare continuous variables. Multiple comparisons were made using analysis of variance. If significant, intragroup and intergroup comparisons were then established with the Mann-Whitney U-test. The statistical package SPSS-PC+ (SPSS Inc., Chicago, IL) was used. Differences were considered significant at the P < 0.05 level and data are presented as median ± SEM and extreme values.
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Results |
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Twenty-eight patients met the eligible criteria (primary inclusion), 18 of them presented a SpO2 <95% and were included in the study and randomized to receive almitrine (n = 9) or a placebo (n = 9).
No significant differences were observed between the placebo group (group P) and the almitrine group (group A) with respect to age, sex ratio, body weight, height, ratio of lung perfusion (right lung perfusion), preoperative arterial blood gases, or spirometric test (Table 1).
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Pulse oxygen saturation evolution is reported in Figure 1. Eight of the 9 patients followed the entire protocol in group A whereas 6 were excluded in group P before the end of the protocol because SpO2 was equal to or <90% (P < 0.05). Treatment was a success (SpO2 was equal to or more than 95% at T2) in 8 patients in group A and 1 in group P (P < 0.01). The excluded patient in group A and the patient who increased his SpO2 in group P had no special characteristics.
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The values for PaO2, PaCO2, heart rate, mean arterial blood pressure, and CI did not differ significantly between groups at T0 (Table 2). Compared with the level found at inclusion (T0), PaO2 increased at T1 (P < 0.02) and T2 (P < 0.02) in group A and did not change in group P. PaO2 values were statistically different between groups at T1 and T2 (P < 0.02). PaCO2, mean arterial blood pressure, heart rate, and CI values did not change throughout the study in each group and no difference was found between groups (Table 2).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrated that IV almitrine improves oxygenation during OLV. The molecular mechanisms of the action of almitrine on the pulmonary vessels combined direct stimulation of chemoreceptors and direct pulmonary vasoconstrictive action. During general anesthesia, pulmonary vasoconstriction is the main property of almitrine. The dose-dependent effect of almitrine has been demonstrated in animals and humans. In anesthetized closed-chest dogs, a model close to OLV in humans, no significant effect was observed between 0.003 and 0.3 µg · kg-1 · min-1 of almitrine, PaO2 increased and hypoxic lung blood flow decreased at 3 µg · kg-1 · min-1 of almitrine (9), and 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 (10). In an animal acute lung injury model, Sommerer et al. (11) have also shown the prime importance of the almitrine dose, as 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. In normal subjects, enhancement of hypoxic pulmonary vasoconstriction is observed at a dose of 4 µg · kg-1 · min-1 (12) and at 8 µg · kg-1 · min-1 in patients with chronic obstructive pulmonary disease (13). Improvement of PaO2 in patients with severe acute respiratory failure by IV almitrine (14–16) seems related to a redistribution of pulmonary blood flow from shunt areas to better-ventilated lung regions as shown by the multiple inert gas technique (17). 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 pulmonary arterial pressure and pulmonary artery resistance index increased dose-dependently from 2 to 16 µg · kg-1 · min-1 (15). When almitrine is used to treat hypoxemia during OLV, treatment must be rapidly efficient, and, because pharmacological knowledge is poor, we pragmatically chose a 12 µg · kg-1 · min-1 almitrine infusion for 10 minutes followed by 4 µg · kg-1 · min-1 almitrine. This bolus dose is larger than that used at the present time in patients with adult respiratory distress syndrome but slightly smaller than that used previously in the same patients (18). However, use of smaller almitrine doses could be a field of interest.
During OLV, PaO2 mainly reflects the ratio of perfusion between both lungs (with a reduced perfusion of the nonventilated, nondependent lung) resulting from three factors: gravity, when surgery is performed in a lateral decubitus position; physical collapse of the nonventilated lung; and hypoxic pulmonary vasoconstriction. Magnitude of the decrease in PaO2 during OLV varies widely among patients because of the many factors involved, especially ventilatory variables (tidal volume, pulmonary hyperinflation) and those that decrease hypoxic pulmonary vasoconstriction (e.g., volatile anesthetics, acid/base imbalance, temperature changes, surgical trauma) (19). Treatment of hypoxemia relies on ventilation with an inspired oxygen fraction of 1.0, continuous positive airway pressure to the nonventilated lung with or without applying positive end-expiratory pressure to the ventilated lung, intermittent manual inflations, high-frequency jet ventilation, and partial ventilation to the nondependent nonventilated lung (3). Another approach is the pharmacological manipulation of pulmonary blood as demonstrated in 1986 by Scherer et al. (20), which showed that pulmonary artery catheter balloon inflation and PGF-2 infusion were equally effective in improving oxygenation during OLV. Attention has focused recently on almitrine, a drug that has a protective effect, because it limits the decrease of PaO2 during OLV either infused alone or associated with inhaled NO (5,6). Intrapulmonary blood flow redistribution from the nonventilated lung towards the ventilated one induced by almitrine could be the mechanism of such prevention.
Almitrine infusion could be the adequate response when a patient remains hypoxemic despite conventional treatment or when application of continuous positive airway pressure to the nonventilated lung can obstruct the surgical field, especially during thoracoscopy for video-assisted thoracic surgery or during thoracic spinal surgery (7). Other indications, arising from the fact that almitrine infusion could avoid the use of large oxygen concentration during OLV, are speculative. High levels of FIO2 represent a potential source of absorption atelectasis increasing shunt (21) and a factor involved in the genesis of post-pneumonectomy pulmonary edema through oxidative stress (22). Finally, almitrine infusion could help to maintain the concentration of inspired oxygen as small as is safely possible when patients have received drugs currently implicated as toxic to the pulmonary system (e.g., bleomycin, mitomycin, carmustine, busulfan, methotrexate, thoracic radiotherapy) (23,24).
A short period of almitrine administration risks pulmonary hypertension and decreased cardiac output, which attenuates the increase in arterial oxygen saturation or partial pressure. In patients with acute respiratory distress syndrome (15,18) and in patients with severe hypoxemic focal lung lesions (25), almitrine increased pulmonary artery pressure with no change in cardiac output. In patients without pulmonary hypertension, pulmonary artery pressure and cardiac output did not change when almitrine infusion began at the initiation of OLV (5). One goal of the present study was to confirm the absence of the deleterious effect of almitrine on cardiac output when the drug is used to treat hypoxemia. We chose to use a noninvasive method of cardiac output measurement because of the design of our study with two steps of patient inclusion: 1) the first step was performed preoperatively as usual, and 2) the second step was intraoperatively when SpO2 was equal to or decreased to <95%. Because we observed some patients before designing our protocol and found that approximately one-half of the patients had a SpO2 <95% when FIO2 was equal to 0.6, it would have been unethical to insert a Swan-Ganz catheter in all patients because right heart catheterization is not usually performed in patients undergoing lobectomy or pneumonectomy in our institution. Although limits of agreement between transesophageal Doppler or thermodilution measurement of cardiac output are large, the use of a Doppler monitor to detect a modification of this variable during a drug infusion is legitimate, as it has been reported that cardiac output variations between two consecutive measures are similar in direction and magnitude using either method (8). Using this noninvasive technique, we did not find any change in cardiac output in half of the patients who completed the study. This was attributable to the difficulty in obtaining a characteristic aortic blood flow signal in the other patients, probably because of the lateral decubitus position.
In conclusion, 12 µg · kg-1 · min-1 almitrine infusion for 10 minutes followed by 4 µg · kg-1 · min-1 almitrine increases arterial oxygenation rapidly during OLV in almost all patients. Almitrine infusion does not change CI but these data are based only on a few observations. Such treatment could be used when a ventilatory strategy to treat hypoxemia during OLV cannot be used.
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References |
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