EP2598130A1 - Pharmaceutical composition for the prevention of perioperative arterial hypotension in humans - Google Patents

Abstract

Pharmaceutical composition for the prevention of perioperative arterial hypotension in humans comprising noradrenalin for intravenous administration.

Description

 PHARMACEUTICAL COMPOSITION FOR THE PREVENTION OF PERTERATORY ARTERIAL HPOTENSION IN HUMAN BEINGS

The present invention relates to a novel pharmaceutical composition comprising norepinephrine for the prevention of intraoperative arterial hypotension, as well as particular administration patterns of this composition.

Intraoperative and postoperative changes in blood pressure are considered to be dangerous in elderly patients or considered "at risk". Thus, in elderly, hypertensive patients undergoing treatment or with aortic stenosis or renal insufficiency hemodialysis, the maintenance of arterial pressure during anesthesia is a therapeutic priority. Any decrease in systolic pressure of 50%, even brief, or 33% for more than 10 minutes, significantly increases the rate of cardiac death during the perioperative period (Goldman L & Caldera, Risks of anaesthesia and elective operation in the hypertensive patients, Anesthesiology, 1979, 50 (4): 285-292).

A French survey showed that among the causes of perioperative deaths attributable to general anesthesia (5.4 per 100,000 anesthesia in France), 39% were the consequence of the inadequate management of intraoperative arterial hypotension (Lienhart A, Auroy Y, Péquignot F et al., Survey of anesthesia-related mortality in France, Anesthesiology 2006; 105: 1087-97).

 More recently, a study of 17,067 non-cardiac surgery patients showed that the one-year mortality risk was statistically related to intraoperative arterial hypotension, proportional to the duration of arterial hypotension (Saager L. et al, Vasopressors May Reduce Mortality Associated with a "Triple Low" of Low Blood Pressure, BIS, and MAC, AS A, October 18,2009).

Finally, another study showed a trend toward 1-year mortality increase with systolic blood pressure (SBP) below 80 mmHg, mean arterial pressure (MAP) below 60 mmHg, or of PAS and diastolic blood pressure (DBP) greater than 40-45%) of their basal values (Bijker JB, van Klei WA, Vergouwe Y et al., Intraoperative hypotension and 1-year mortality after noncardiac surgery, Anesthesiology 2009 111: 1217-26). In addition to increasing the risk of death following surgery, the occurrence of intraoperative hypotension is also responsible for the appearance of postoperative side effects. In particular, it significantly increases the risk of postoperative renal insufficiency in the patient (Kheterpal S, Dip KK, Englesbe MJ, O'Reilly M, AM Shanks, Fetterman DM, et al., Predictors of postoperative acute renal failure after noncardiac surgery in patients with previously normal renal function, Anesthesiology, 2007 Dec; 107 (6): 892-902). The occurrence of intraoperative arterial hypotension also causes postoperative complications, including non-cardiac surgery, such as systemic inflammatory response syndrome (SIRS) or increased risk of myocardial infarction and stroke. brain in the postoperative period.

In patients, the prevention of intraoperative hypotension to maintain blood pressure close to the initial blood pressure, ie before anesthesia, is therefore essential to reduce the risk of death and to reduce the risk of death. improvement of the operating sequences.

Several methods are currently used to try to treat low blood pressure during anesthesia. The use of ephedrine and volume expansion are thus commonly used for the intraoperative treatment of arterial hypotension.

Ephedrine, systematically prepared and available in the anesthetic range, is usually the first vasopressor used to treat low blood pressure. Ephedrine injected as an intravenous bolus of 3 to 6 mg has a rapid effectiveness. However, its action can not be sustainable. Indeed, ephedrine allowing the release of norepinephrine from the peripheral sympathetic endings, tachyphylaxis can settle quickly once the nerve endings depleted in norepinephrine.

Volume expansion, also referred to as vascular filling, is part of the therapeutic arsenal used daily by anesthetists. Clinical practice recommends the infusion of 50 to 200 ml of a colloid or 200 to 500 ml of crystalloid in 10 to 15 minutes in order to compensate for vasculitis induced by anesthesia. But the hemodynamic effect is neither immediate nor rapidly reversible: inflation The resultant hydrosodée is responsible for hypertensive growth during the anesthetic recovery phase and delays in the resumption of transit in the abdominal surgery suites.

At the time of the present invention, there is no satisfactory treatment to prevent the phenomena of intraoperative arterial hypotension, thus allowing the maintenance of the patient's blood pressure to the level at which it was before anesthesia or to a very close level (less than 40% drop) of it.

There is therefore a definite need for such treatment. However, the development of such a treatment proved very difficult, it must:

 - act immediately on the tension of the patient in order to act from the beginning of the anesthesia,

- allow to obtain a lasting effect to extend during all the anesthesia,

- be perfectly controllable in case of overdose to avoid any significant hypertension that could cause irreversible damage,

- and finally, have a rapidly reversible effect as soon as it stops.

Norepinephrine, or norepinephrine, is an organic neuromediator compound that acts as an adrenergic hormone and neurotransmitter. It's a catecholamine like dopamine or adrenaline. It is mainly released by the nerve fibers of the nervous system (sympathetic) and acts as a neurotransmitter in the effector organs. She plays a role in attention, emotions, sleep, dreams and learning. It is also the metabolic precursor of adrenaline. Norepinephrine is marketed by various pharmaceutical companies in the form of a concentrate for solution for infusion containing 2 mg / ml noradrenaline tartrate or 1 mg / ml norepinephrine base.

In intravenous infusion, norepinephrine is used in intensive care in the emergency treatment of cardiovascular collapse and for the restoration and maintenance of blood pressure.

In gastric local irrigation, norepinephrine is useful in the treatment of gastrointestinal bleeding, in addition to the usual treatments. According to the Summary of Product Characteristics (SPC), it is recommended to initially administer doses of norepinephrine to the patient. Dosages up to 3 to 5 Recommended for the treatment of septic shock or haemorrhagic shock. In addition, it is also recommended that norepinephrine should not be combined with halogenated anesthetic gas or severe ventricular arrhythmias may occur.

The use of norepinephrine to prevent intraoperative arterial hypotension has never been described.

In intravenous levosimendan-norepinephrine combination during off-pump coronary artery bypass grafting in a hemodialysis patient with severe myocardial dysfunction, Journal of Cardiothoracic Surgery, 2010, 5: 9, G. Papadopoulos et al. report the combined administration of levosimendan, a positive inotropic agent known to cause low blood pressure, and norepinephrine to a single patient with heart failure. In the case reported, the administration of norepinephrine was decided by the physician after the anesthetic induction phase and after the physician found on transoesophageal ultrasound (TEE) a deterioration of myocardial contractility with dilatation. ventricles, which required treatment with levosimendan, known to have hypotension as a side effect. Thus, in the case of this patient, norepinephrine was administered solely to overcome the hypotensive effects of levosimendan, in no case within the framework of the prevention of intraoperative arterial hypotension. In addition, the French Society of Anesthesia Resuscitation (SFAR) advises against the use of norepinephrine in the context of anesthesia, considering that adrenaline is the vasoactive agent of choice in the severe states of shock occurring during treatment. a general anesthesia, norepinephrine resulting in intense vasoconstriction affecting the entire arterial and venous system, this effect being dose-dependent. Thus, an excessive dose of norepinephrine leads to an increase in vascular resistance and, at the same time, an impairment of ventricular function with a decrease in cardiac output (SFAR, Huet O. & Duranteau J. "Place of vasoactive agents in non-cardiac surgery", Conference of update, 1999, p.161-173). It has been discovered, however, completely unexpectedly, that the norepinephrine-based pharmaceutical composition according to the present invention makes it possible to prevent intraoperative arterial hypotension with almost immediate action, lasting, controllable and rapidly reversible.

 It has also been discovered that the administration of this pharmaceutical composition for the prevention of intraoperative arterial hypotension can be done concomitantly.

 administering an anesthetic product such as intravenous propofol,

 but also to the administration of a halogenated anesthetic gas such as sevoflurane without risk of disturbance of the cardiac rhythm,

and whatever the morphine derivative used (sufentanil, remifentanil ...).

Thus, the present invention relates to a pharmaceutical composition for the prevention of intraoperative arterial hypotension in humans comprising norepinephrine for intravenous administration.

The composition according to the invention allows the maintenance of the intraoperative blood pressure in the treated patient to a level equivalent to that measured before anesthesia.

 The effect of the composition according to the invention is almost immediate, durable without tachyphylaxis, reversible rapidly upon cessation of injection, and controllable in case of overdose by injection of nicardipine calcium inhibitor such as the LOXEN® bolus at a dose of 1 mg.

 The composition according to the invention can be administered for any type of anesthesia, whether an anesthetic product administered intravenously such as propofol and / or a halogenated anesthetic gas such as sevoflurane, and whatever is used. the morphine derivative used (sufentanil, remifentanil ...).

 The composition according to the invention thus makes it possible to complete, reinforce and improve the "therapeutic arsenal" usually used and recommended for the prevention of intraoperative hypotension, namely the use of ephedrine and volume expansion.

Finally, the composition according to the invention makes it possible, consequently, to limit the occurrence of postoperative side effects associated with the occurrence of an intraoperative hypotension such as renal insufficiency, inflammatory bowel syndrome, systemic response (SIRS) or the increased risk of myocardial infarction and stroke in the postoperative period. In the context of the present invention:

 - "peroperative arterial hypotension" means any decrease in systolic blood pressure or mean arterial pressure that may occur during anesthesia phase, in particular general anesthesia, including in a resuscitation phase, locoregional anesthesia or an epidural, in comparison with the patient's blood pressure prior to anesthesia;

 - "Prevention of intraoperative hypotension" means maintaining the patient's systolic or mean blood pressure:

 at a value close to 40% of his systolic or preoperative mean blood pressure, and / or

at a systolic blood pressure greater than or equal to 80 mmHg or at an average arterial pressure greater than or equal to 60 mmHg (Samain E, Pili-Floury S, Barrucand B., Control of the blood pressure of the heart rate in anesthesia 2009; l ^th National Congress of anesthesia and intensive Care Basics, Elsevier Publishing, pages 6 and 7).

 the term "pharmaceutically acceptable salt" of an active ingredient means any salt of addition of said active ingredient with an inorganic or organic acid by the action of such an acid in an organic or aqueous solvent such as an alcohol, a ketone, an ether or a chlorinated solvent, and which is acceptable from a pharmaceutical point of view;

 the term "pharmaceutically acceptable derivative" of an active ingredient is understood to mean any "prodrug" or "metabolite" of said active ingredient, as well as a pharmaceutically acceptable salt;

 - by "active drug" means any compound whose biotransformation in the body results in the active ingredient;

 - "metabolite" of an active ingredient means any intermediate product resulting from the transformation of said active ingredient in the body during a metabolic process; noradrenaline (or norepinephrine) means 4 - [(Li) -2-amino-1-hydroxyethyl] benzene-1,2-diol, of chemical structure:

and pharmaceutically acceptable salts or derivatives thereof, including noradrenaline tartrate, noradrenaline bitartrate and noradrenaline hydrochloride; ephedrine means (1RS, 2SR) -2- (methylamino) -1-phenylpropan-1-ol, of chemical structure:

and pharmaceutically acceptable salts or derivatives thereof, including ephedrine hydrochloride;

 Atropine means 8-methyl-8-azabicyclo [3.2.1] oct-3-yl 3-hydroxy-2-phenylpropanoate of chemical structure:

and pharmaceutically acceptable salts or derivatives thereof, including atropine sulfate;

 the term "continuous administration" is intended to mean the administration of a pharmaceutical composition according to a therapeutic administration scheme determined in an unlimited manner and not sequenced or spaced apart over time, that is to say without interruption of treatment;

the term "bolus administration" is understood to mean the intravenous administration, possibly repeatedly, of a single dose of a pharmaceutical composition.

The present invention therefore relates to a pharmaceutical composition as defined above for the prevention of intraoperative arterial hypotension in humans. Preferably, the subject of the present invention is a pharmaceutical composition as defined above comprising from 0.1 μg / ml to 100 μg / ml noradrenaline, preferably from 0.5 μg / ml to 50 μg / ml noradrenaline, preferably still 1 μg / ml to 10 μg / ml noradrenaline.

The pharmaceutical composition according to the present invention may be formulated in any dosage form necessary for its intravenous administration such as, for example, a concentrate for solution for infusion or a solution for infusion ready for use. The pharmaceutical compositions according to the present invention may therefore comprise, in addition to the principal action, any adjuvant of a pharmaceutically acceptable formulation known to those skilled in the art and which is necessary for the preparation of the pharmaceutical composition in the desired form. . By way of example, mention may in particular be made of sodium metabisulfite, hydrochloric acid, sodium hydroxide or inert gases such as nitrogen or argon).

The pharmaceutical composition according to the present invention can be administered to any patient under anesthesia or preparing to undergo anesthesia. Preferably, the pharmaceutical composition according to the present invention is administered to patients in whom the intraoperative hypotension will be the most pronounced and the most deleterious such as elderly, hypertensive or coronary patients. The pharmaceutical composition according to the invention thus makes it possible to prevent intraoperative arterial hypotension in humans. The pharmaceutical composition according to the present invention can be administered to the patient according to different delivery schedules. However, it has been found that a regimen of administration of the composition according to the present invention is particularly effective in preventing intraoperative arterial hypotension in humans. Thus, the present invention also relates to a pharmaceutical composition as defined above for a continuous administration to humans of 0.005 μg / kg / min at 0.5 μg / kg / min of nor adrenaline. This administration scheme allows an efficient, precise and progressive administration of norepinephrine, preventing hypotension without risk of induction of deleterious arterial hypertension.

Preferably, the subject of the present invention is a pharmaceutical composition as described above for a continuous administration to humans of 0.01 μg / kg / min at 0.1 μg / kg / min, more preferably 0.02 μg / kg / min. μg / kg / min at 0.08 μg / kg / min noradrenaline.

The pharmaceutical composition of the present invention may be administered at any time during anesthesia. Preferably, the composition according to the invention is administered to the patient a few minutes before anesthetic induction or at the same time. as it is and is readjusted as the procedure progresses to the moment of waking when the patient's tension rises parallel to the anesthetic waking, allowing the norepinephrine to be weaned while maintaining an optimal level of tension. Most preferably, the composition according to the invention is administered to the patient from 1 to 5 minutes before the anesthetic induction, more preferably 2 to 4 minutes before the anesthetic induction.

The composition according to the present invention can be administered to the patient by any effective means known to those skilled in the art. In particular, an isolated infusion may be used to prevent the accidental administration of a bolus. To do this, a proximal lane of a multi-lane central venous catheter, or a different peripheral vein separated from the peripheral venous route used for anesthesia, or a three-way valve located directly on the catheter may be used. venous peripheral at the end of the infusion tubing.

The present invention also relates to the use of a pharmaceutical composition as defined above for the preparation of a medicament for preventing intraoperative arterial hypotension in humans. The present invention also relates to the use of a pharmaceutical composition as defined above for the preparation of a medicament for preventing intraoperative arterial hypotension in humans, said medicament being administered continuously intravenously so that from 0.005 μg / kg / min to 0.5 μg / kg / min, preferably from 0.01 μg / kg / min to 0.1 μg / kg / min, more preferably 0.02 μg / min. kg / min at 0.08 μg / kg / min of norepinephrine are administered to said human being.

The present invention also relates to a method of preventive treatment of intraoperative arterial hypotension in humans by administering a pharmaceutical composition as defined above to said human being.

The subject of the present invention is also a method for the preventive treatment of intraoperative arterial hypotension in humans by the continuous administration of a pharmaceutical composition as defined above to said human being, said composition being administered so that of 0.005 μg / kg / min at 0.5 μg / kg / min, preferably from 0.01 μ§ / 1¾ / ηιίη to 0, 1 μ / 1ί / ηιίη, more preferably from 0.02 μ / 1ί / ηιίη to 0.08 μ / 1ί / ηιίη of norepinephrine are administered to said human being .

Finally, although the composition according to the present invention can be administered alone, joint, separate or sequential administration with ephedrine may also be considered. Thus, the subject of the present invention is also a pharmaceutical product containing:

 a pharmaceutical composition as defined above; and

 a pharmaceutical composition comprising from 0.001 to 0.01 mg / ml, preferably from 0.002 to 0.005 mg / ml of atropine, and / or a pharmaceutical composition comprising from 1 to 10 mg / ml, preferably from 1 to 5 mg ml of ephedrine;

as a combination product (or pharmaceutical kit) for simultaneous administration, separate or spread over time,

for the prevention of intraoperative arterial hypotension in humans.

Preferentially, the pharmaceutical product according to the present invention contains a pharmaceutical composition as defined above and a pharmaceutical composition comprising from 0.001 to 0.01 mg / ml, preferably from 0.002 to 0.005 mg / ml of atropine.

Most preferably, the pharmaceutical product according to the present invention allows a continuous administration of the pharmaceutical composition according to the invention of 1 to 5 minutes (preferably 2 to 4 minutes) before the anesthetic induction until the moment of the waking, and the bolus-separated administration of the pharmaceutical composition comprising atropine just after the anesthetic induction.

The present invention is illustrated in a nonlimiting manner by the following examples. Example 1 Use of noradrenaline in the context of general and / or locoregional anesthesia in non-cardiac surgery of the adult

1. Study The study involved 1534 patients who underwent intraoperative hemodynamic optimization with the use of norepinephrine (as norepinephrine tartrate). for maintenance of blood pressure under general anesthesia in non-cardiac surgery of the adult,

2. Experimental protocol

2-1. Hemodynamic monitoring

Hemodynamic monitoring is performed non-invasively with blood pressure taken automatically every 2 minutes during anesthetic induction, then every 5 minutes during periods of hemodynamic stability.

2-2. Therapeutic Conduct

Norepinephrine is used according to the following protocol.

Administration of norepinephrine by continuous infusion with the solution titrated at 10 μg / ml.

This solution is injected:

 · On the one hand in continuous infusion, in automatic pushing syringe, whose speed will be modulated according to the weight of the patient, his age, his initial "tension state" (notion of treated or untreated arterial hypertension), the presence or absence of epidural anesthesia associated with general anesthesia. • On the other hand as an isolated infusion to avoid inducing a bolus of NA when injecting another drug into the infusion line. This isolated infusion is connected either to an additional venous catheter independent of the venous approach used for anesthesia, or to a multi-lumen catheter of a central venous line, or to a three-way valve located between the peripheral venous catheter and the end of the infusion tubing.

The recommended dosages are from 0.02 to 0.08 μg / kg / min of norepinephrine.

The appropriate dosage is that which allows to obtain a blood pressure close to 20% of the preoperative blood pressure of the patient, and a systolic blood pressure> 100 mmHg. In the case of general anesthesia, administration of norepinephrine as a continuous infusion with the titrated solution at 10 μg / ml should be started 3 to 4 minutes before anesthetic induction to prevent arterial hypotension induced by anesthesia. The inefficacy of norepinephrine at these dosages must make look for another etiology to hypotension: a delay in compensation for intraoperative hydroelectrolytic losses, vena cava compression, septic shock, anaphylactic shock.

Norepinephrine withdrawal is during the anesthetic recovery phase by progressively decreasing noradrenaline administration dosages based on the return to preoperative blood pressure.

3. Parameters of the study 3-1. The patients

The study involved 1534 patients aged 15 to 102 years (mean age 56 years), average weight 72 kg (range 33 to 163 kg), mean preoperative blood pressure 138 mmHg (95 to 200 mmHg) ).

ASA (American Society of Anesthesiologists) classification: 38.4% of patients are ASA I (ie, "normal patient"), 42.2% are ASA II (ie, Patient with moderate systemic abnormality "), 16.0% are classified ASA III (ie" patient with severe systemic abnormality "), and 3.4% are classified as ASA IV.

Age: all ages from 15 to 102 years; the average age is 56 years old. 25.0%) are over 70 years of age, 8.5% of whom are over 80 years of age.

Patient history:

- 30.1% of patients are smokers (from 15 to 50 year packs)

 - 32.9% are hypertensive treated

 - 12.6% are coronary treated

 - 8.4% are diabetic treated

- 0.98% are renal insufficiency hemodialysis. 3-2. Surgical interventions

The nature of the interventions is varied:

 - 10.6% are hemorrhagic orthopedic surgical procedures;

- 18.4% are non-hemorrhagic orthopedic surgery procedures;

 - 17.9% are laparotomy procedures in digestive, urological or spinal surgery by anterior route;

 - 11, 2% are ENT surgeries;

 - 5.9% are laparoscopic procedures;

- 12.2% are vascular or thoracic surgery;

 - 9.3% are plastic surgery and stomatology interventions.

 - 14.5% are various interventions.

3-3. Anesthesia

The type of anesthesia is varied:

 - 73.8% are isolated general anesthesia;

 - 15.7% are general anesthesia associated with epidural anesthesia;

 - 9.1% are general anesthesia associated with locoregional anesthesia by peripheral block;

 - 1.4% are isolated rachianesthesia without general anesthesia.

The procedure for induction of general anesthesia is identical for all patients: patients receive 0.2 μg / kg of sufentanil, after 3 minutes 1, 5 to 3 mg / kg of propofol, then 0.15 mg / kg of cisatracurium.

 Patients are intubated 3 minutes after curare injection and ventilated at 8ml / kg theoretical weight.

 Maintenance of anesthesia is provided by sevoflurane. Intraoperative analgesia is managed by continuous injection of remifentanil and / or repeated injection of sufentanil.

3-4. Noradrenaline administration

The administration by continuous infusion of norepinephrine in solution to 10 μg / ml noradrenaline is done 4 minutes before anesthetic induction. The dosages used are generally between 0.02 and 0.08 μg / kg / min. So :

 - 47.9% of the injections are at a dosage between 0.04 and 0.06 μg / kg / min;

- 22.7% of injections are at a dosage lower than 0.04 μg / kg / min in obese patients; and

 21.6% of the injections are at a dosage of between 0.06 and 0.08 μg / kg / min. Only 7.8% of the injections are at a dosage between 0.08 and 1 μg / kg / min in very old patients, or renally impaired hemodialysis. The average duration of administration of continuous norepinephrine infusion is 105 min (range 15 to 420 min), from anesthetic induction to weaning in the recovery room.

Weaning from the continuous infusion of noradrenaline solution at 10 μg / ml is done during the anesthetic anesthetic phase by gradually decreasing the dosages of administration of norepinephrine as a function of the return to preoperative blood pressure.

In all cases, the weaning was done without incident and quickly from the waking phase.

In 1, 4% of the cases where the weaning could be done only after vascular filling, expressing a delay of vascular filling. 3-5. Research of adverse effects

Clinically: non-invasive monitoring of blood pressure is performed every 2 minutes during anesthetic induction, then every 5 minutes during periods of hemodynamic stability.

The quality of the intraoperative haemostasis was systematically noted. As long as the arterial pressure did not exceed the patient's initial arterial pressure, there was no excessive bleeding peroperatively.

The following items are routinely sought and scored within the first 24 hours postoperatively: restless agitation, nausea and / or postoperative vomiting (PONV). Biologically: the determination of troponin was carried out at J1 in 26.0% of the patients judged to be at risk: 99.87% are at zero, 1 patient has a troponin dose at 0.04 and a patient at 0 0.5 ng / ml (signifcativity threshold is 0.4 ng / ml). These patients were checked again and their rate normalized on D2.

The determination of urea and creatinine at D0 and D1 was made in 26.0% of patients judged to be at higher risk. There is no change in renal function on the results obtained.

On the radiological level: venous doppler of the lower limbs is performed in patients at risk on D4 (26.0% of patients): five cases of superficial venous thrombosis were noted.

4. Experimental results 4-1. Depending on the patient

In elderly patients the risk is vital: the maintenance of blood pressure is a therapeutic priority. Norepinephrine in anesthesia was first used in these patients for safety reasons: a decrease in systolic blood pressure of 50%), even a brief one, or 33% for more than 10 minutes increases cardiac death. during the perioperative period. A study of 17,067 non-cardiac surgery patients showed that the one-year mortality risk was statistically related to intraoperative arterial hypotension, proportional to the duration of arterial hypotension (Saager et al., Vasopressors May Reduce Mortality Associated with a "Triple Low" of Low Blood Pressure, BIS, and MAC, ASA, 2009, 50 (4): 285-292).

8.5%) of patients in the study are over 80 years old, the prognosis has been preserved and the follow-up has been neurologically, cardiac and respiratory simple. According to this study, noradrenaline dosages used in the very old patient to maintain blood pressure close to baseline arterial blood pressure are higher than those used in younger patients.

In hypertensive patients treated: the notion of prevention and correction of hypotension is even more important. According to this study, norepinephrine dosages used to maintain near-pres- arterial levels are higher than those used in non-hypertensive patients.

In the patient with aortic stenosis: five cases of elderly patients with tight aortic stenosis and fracture of the femoral neck, the use of norepinephrine controlled intraoperative blood pressure during surgery. general anesthesia without cardiac incident.

In hemodialysis patients with renal failure: they accumulate cardiovascular risk factors and for these patients, volume filling should be avoided, norepinephrine injection has made it possible to control blood pressure, but with higher administration doses: 0.05 at 0.08 μg / kg / min.

In young patients without antecedents: intraoperative changes in blood pressure are considered well tolerated, yet low doses of noradrenaline 0.02 μg / kg / h are sufficient to optimize blood pressure and provide a better quality of awakening: better lucidity and almost disappearance of postoperative nausea and vomiting. 4-2. Depending on the intervention

Laparoscopic procedures: Norepinephrine injection, initiated during anesthetic induction, was reduced and discontinued as blood pressure increased with laparoscopic insufflation, except in a few cases ( 12.5%) where norepinephrine doses were decreased but maintained at low dose (0.025 to 0.04 μg / kg / min) during laparoscopy

Cases of haemorrhagic surgery: In this study norepinephrine injection at these doses and the maintenance of blood pressure close to the initial arterial pressure did not increase peroperative bleeding since the level of anesthesia and analgesia are high enough. Thus the very fact of being able to maintain a sufficiently high level of anesthesia and analgesia without the risk of hypotension seems to be a guarantee of less peroperative bleeding.

In the event of sudden blood loss, the use of norepinephrine infusion makes it possible to maintain an infusion pressure while waiting for a volume expansion adapted to blood loss. Laparotomy surgery: the combination of general anesthesia and epidural anesthesia increases the risk of peroperative arterial hypotension. The injection of norepinephrine at these doses allowed to control the blood pressure for a prolonged period (up to 400 min) without tachyphylaxis and without excess vascular filling: many studies agree to advocate the reduction of perioperative volume appears to decrease the time to resumption of transit, shorten the duration of hospitalization and reduce cardiac and infectious complications. The possibility of preventing intraoperative hypotension improves the level of anesthesia without risk of arterial hypotension, thus avoiding underdosage in anesthesia responsible for intraoperative arterial hypertension. 4-3. Adverse effects

Hypertension (HTA): Hypertensive access should not occur at the recommended dosages. It is more related to insufficient level of anesthesia and analgesia. In the face of hypertensive access, the measures taken were respectively:

- strengthen Γ anesthesia and analgesia,

 - decrease the rate of administration of norepinephrine (short duration of action),

- and, if necessary as a last resort, use vasodilator drugs of the calcium channel blocker type: NICARDIPINE (LOXEN®) at a dose of 1 mg bolus (26 cases). Bradycardia: the use of a vasoconstrictor causes activation of the baroreflex system resulting in bradycardia. This bradycardia is accentuated in patients treated with betablockers and in patients analgesic with a morphine of the type REMIFENTANIL (ULTIVA®).

 Atropine is in practice used (in 90% of the cases in our study) in a preventive way as soon as the pulse of the patient starts to slow down, at the end of anesthetic induction.

Renal function: This is a theoretical risk of norepinephrine at usual doses used in intensive care. On the contrary, in the context of the study at the proposed dosages in anesthesia, in all the patients at potential renal risk, the urea and creatinine measurements at day 0 and day 1 showed in all cases a decrease in their value postoperatively at Jl. There was a marked increase in intraoperative urinary output, which reflects a good functioning of renal function. No other adverse effects were identified during the study. In particular, the absence of morbidity is a guarantee of security. 4-6. Advantages

Maintenance of blood pressure: the maintenance of blood pressure is the goal in this study of the use of norepinephrine, it is a guarantee of safety in the elderly, hypertensive, coronary.

 The effect of norepinephrine on blood pressure is immediate, short but without tachyphylaxis, durable in continuous injection, reversible quickly.

Alternative to vascular filling: Vascular filling must know how to remain moderate in order to avoid any harmful overload. The absence of morbidity following the use of norepinephrine in this study makes it a good alternative to vascular filling.

Post Operative Nausea (PONV): None of the patients in whom blood pressure was controlled with norepinephrine injection experienced vomiting. The few nauseas (1, 2% vs. 30%> traditionally) were controlled by ZOPHREN. Some patients with a history of PONV (18%) were pleased to note that they did not have PONV this time.

Lucidity upon waking anesthetic and absence of agitation: were noted in all patients, regardless of the duration of intervention and the age of the patient.

Venous thromboembolic diseases: only 0.32% of distal peripheral venous thrombosis complications versus 5 to 40%, depending on the type of surgery performed. The absence of thromboembolic complications is notable. Venous Doppler is routinely performed on D4 in at-risk patients. On the other hand, the reduction of thromboembolic risk is obtained without increasing the risk of bleeding. 4-7. Conclusion

The noradrenalme composition according to the invention thus makes it possible to complete, reinforce and improve the "therapeutic arsenal" usually used and recommended for the prevention of intraoperative arterial hypotension such as the use of ephedrine and volume expansion.

Example 2 - Practical use of the norepinephrine composition according to the present invention

The following table is a practical example of the use of the norepinephrine composition (in the form of noradrenaline tartrate) according to the present invention for determining the rate of administration of the syringe (in ml / h) containing the norepinephrine solution to 10 μ§ / ι 1 depending on the amount of noradrenaline administered (in μg / kg) and patient weight (in kg).

Claims

A pharmaceutical composition for the prevention of intraoperative arterial hypotension in humans comprising norepinephrine for intravenous administration. 2. Pharmaceutical composition according to claim 1, characterized in that it comprises from 0.1 μ ^ ηύ to 100 μ ^ ηύ norepinephrine. 3. Pharmaceutical composition according to claim 2, characterized in that it comprises from 0.5 μ ^ ηύ to 50 μ ^ ηύ norepinephrine. 4. Pharmaceutical composition according to claim 3, characterized in that it comprises from 1 μ ^ ηύ to 10 μ ^ ηύ norepinephrine. 5. Pharmaceutical composition according to any one of claims 1 to 4, for a continuous administration to humans of 0.005 μ§ / 1¾ / ιηίη to 0.5 μ ^^ ηήη norepinephrine. 6. Pharmaceutical composition according to claim 5, for a continuous administration to humans of 0.01. noradrenaline. 7. Pharmaceutical composition according to claim 6, for a continuous administration to humans of 0.02 μ ^^ ηήη to 0.08 μ ^^^^ nadrenaline. 8. Pharmaceutical composition according to one of claims 1 to 7, characterized in that the composition is administered to the patient from 1 to 5 minutes before anesthetic induction until waking. 9. Pharmaceutical product containing:  a pharmaceutical composition as defined in one of claims 1 to 7; and a pharmaceutical composition comprising from 0.001 to 0.01 mg / ml atropine and / or a pharmaceutical composition comprising from 1 to 10 mg / ml ephedrine; as a combination product for simultaneous, separate or spread administration over time for the prevention of intraoperative arterial hypotension in humans. 10. Pharmaceutical product according to claim 9, containing a pharmaceutical composition as defined in one of claims 1 to 7 and a pharmaceutical composition comprising from 0.001 to 0.01 mg / ml of atropine. 11. Pharmaceutical product according to claim 10, for a continuous administration of the composition as defined in one of claims 1 to 7 from 1 to 5 minutes before anesthetic induction until the moment of awakening, and the separate administration. in bolus of the pharmaceutical composition comprising atropine just after the anesthetic induction.