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CẤP CỨU NGỘ ĐỘC VÌ QUÁ LIỀU OPIACÉS (DẪN CHẤT CỦA THUỐC PHIỆN)
                       Nguyễn Văn Bích (Médecin urgentiste, Diplômé de la Faculté de Médecine de Marseille)
                       Võ Khôi Bửu (BS chuyên khoa 1 Nội tổng quát)
 
                                                                    
* Ngộ độc vì quá liều opiaciés là một cấp cứu nội khoa quan trọng cần sự can thiệp của toán cấp cứu di động ngay tại nơi xảy ra tai nạn, sau đó bệnh nhân phải được chuyển gấp đến khu cấp cứu nội khoa.
* Opiacés bao gồm những chất xuất phát từ thuốc phiện (dérivés de l'opium),  những chất bán tồng hợp (semi-synthétiques), hay tổng hợp(synthétiques) có tính chất chung là tác động ở những thụ thể thuốc phiện (récepteurs opiacés) tại não gây nên sự phụ thuộc thuốc (nghiện) sau một thời gian sử dụng (ngoại trừ lopéramide vì chất nầy không thấm qua được hàng rào máu-não). Những opiacés thông thường là morphine, codéine, héroine, hydromorphine, oxymorphine, méthadone, papavérine, narcotine, buprénorphine ...

* Suy hô hấp cấp tính là mối lo ngại hàng đầu ở các trường hợp ngộ độc opiacés. Vì thế, điều trị suy hô hấp cấp tính là trị liệu cấp cứu chủ yếu.

* Thuốc cấp cứu cần thiết: Naloxone (Narcan, Nalone, Narcanti): ống 1ml chứa 0,4 mg, dạng tiêm tĩnh mạch, tiêm bắp hoặc tiêm dưới da.

* Dụng cụ cấp cứu cần thiết: các dụng cụ cấp cứu, hồi sức về tim mạch và hô hấp.

* Chẩn đoán:
    -Trường hợp ngộ độc đơn thuần (không biến chứng): thường dễ chẩn đoán dựa vào các triệu chứng sau:  rối loạn tri giác (troubles de conscience), nhịp thở chậm (thường <12 lần/ phút), con ngươi thu nhỏ (myosis) (có thể nhỏ bằng đầu kim: en tête d'épingle). Có thể thấy tím (cyanose). Tuy nhiên, bệnh nhân còn phản ứng với kích thích đau.
    -Trường hợp ngộ độc đã có biến chứng: hôn mê, co giật, trụy tim mạch, thân nhiệt thấp (hypothermie), nhiễm trùng phổi, phù phổi (œdème pulmonaire non cardiaque), ly giải cơ (rhadomyolyse).
 
* Điều trị cấp cứu trường hợp ngộ độc đơn thuần (không biến chứng): Chủ yếu là điều trị suy hô hấp cấp tính, bao gồm:
  . Dưỡng khí liệu pháp (oxygénothérapie), với mặt nạ (masque) hoặc qua ống nội khí quản (intubation), hay máy thở nếu cần.
  . Điều trị đặc hiệu (traitement spécifique): dùng thuốc giải độc: Naloxone.
  Về mặt thực hành, tùy theo hoàn cảnh và phương tiện trang bị mà ưu tiên cho một trong hai liệu pháp trên. Nên dành ưu tiên cho dưỡng khí liệu pháp vì hiệu quả cao, ít gây biến chứng. Dưỡng khí liệu pháp đơn độc thường giúp bệnh nhân lấy lại tình trạng tri giác (état de conscience) một cách khả quan. Trong mọi trường hợp, mục đích  là hồi phục sự hô hấp hiệu quả của bệnh nhân.
  Naloxone bao giờ cũng phải được pha loãng trước khi dùng (pha 0,4 – 0,8 mg trong 10 ml trong NaCl 0,9% hay Dextrose 5%: tiêm  0,2 mg vào tĩnh mạch cứ mỗi 2 phút. Ngừng tiêm khi nhịp thở khoảng 10 – 12 /phút và khi có sự tái xuất hiện các phản xạ ở đường hô hấp trên – đó là những phản xạ gây ra từ những kích thích vùng tỵ hầu (rhino-pharynx) khi đưa 1 tubulure qua đường mũi, và vùng khẩu hầu (oro-pharynx) khi dùng cây đè lưỡi (abaisse-langue). Hiệu quả điều trị có thể thấy ngay 1 – 2 phút sau khi tiêm thuốc. Nếu sau khi tiêm 1,2 mg mà vẫn không có hiệu quả thì nên bắt đầu xem xét lại chẩn đoán, hãy nghĩ đến những bệnh não do thiếu dưỡng khí (lésions cérébrales hypoxiques), hay quá liều với nhiều thuốc hỗn hợp. Có thể dùng liều lượng cao hơn 1,2 mg.
 
* Các xét nghiệm cận lâm sàng:
  - X quang phổi, đo lường các khí trong máu động mạch (gazométrie artérielle), điện tâm đồ, ion đồ (ionogramme), creatinin máu ... Tuy nhiên không có xét nghiệm nào là cần thiết trước khi khởi đầu các trị liệu khẩn cấp nêu trên.
 
  - Xét nghiệm phân tích chất độc có thể xác nhận có morphiniques trong nước tiểu. Tuy nhiên, không tìm thấy được chất độc trong trường hợp ngộ độc buprénorphine.

  - Xét nghiệm tìm các dược chất hướng thần kinh (psychotropes) (như amphétamines, cocaine, barbituriques, benzodiazépines – canabis, marjuana, haschisch...) lúc nào cũng cần thiết.
 
 * Ghi chú:   
    Các trị số bình thường của khí trong máu (Gazométrie artérielle normale):
    - P_aO₂: tùy thuộc vào tuổi của bệnh nhân (P_aO₂ tính bằng mmHg = 104,2 - 0,27 × tuổi)
    - P_aCO₂: 35 - 44 mmHg ;
    - Bicarbonates (HCO₃^–) : 22 - 28 mmol/L
    - S_aO₂ : 95-100 %

 
Cảm ơn trước mọi góp ý, đóng góp kinh nghiệm tri liệu  của các bạn và đồng nghiệp, xin gởi về :
docteur_nguyen@yahoo.fr  hay  khoi1952buu@yahoo.com
 
* Tài liệu đọc thêm:
(http://www.rxlist.com/narcan-drug.htm)
Naloxone hydrochloride, a narcotic antagonist, is a synthetic congener of oxymorphone. In structure it differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group.
It has the following molecular formula C19H21NO4·HCl with a molecular weight of 363.84.
The chemical name for naloxone hydrochloride is: (-)-17-Allyl-4, 5a-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride
Naloxone hydrochloride occurs as a white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform.
Naloxone Hydrochloride Injection is a sterile solution intended for intramuscular, subcutaneous or intravenous use. Each mL contains naloxone hydrochloride 400 micrograms (0.4 mg), sodium chloride 8.6 mg, methylparaben 1.8 mg and propylparaben 0.2 mg in Water for Injection. pH 3.0-4.5; hydrochloric acid and/or sodium hydroxide used, if needed, for pH adjustment. Sealed under nitrogen.
INDICATIONS
Naloxone Hydrochloride Injection is indicated for the complete or partial reversal of narcotic depression, including respiratory depression, induced by opioids including natural and synthetic narcotics, propoxyphene, methadone and the narcotic-antagonist analgesics: nalbuphine, pentazocine and butorphanol. Naloxone Hydrochloride Injection is also indicated for the diagnosis of suspected acute opioid overdosage.
DOSAGE AND ADMINISTRATION
Naloxone Hydrochloride Injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration, and this route is recommended in emergency situations.
Since the duration of action of some narcotics may exceed that of naloxone, the patient should be kept under continued surveillance, and repeated doses of naloxone hydrochloride should be administered, as necessary.
Intravenous Infusion
Naloxone Hydrochloride Injection may be diluted for intravenous infusion in 0.9% Sodium Chloride Injection or 5% Dextrose Injection. The addition of 2 mg of naloxone hydrochloride in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused solution must be discarded. The rate of administration should be titrated in accordance with the patient's response.
Naloxone Hydrochloride Injection should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No drug or chemical agent should be added to Naloxone Hydrochloride Injection unless its effect on the chemical and physical stability of the solution has first been established.
Usage in Adults
Narcotic Overdose-Known or Suspected: An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions is not obtained, it may be repeated at 2 to 3 minute intervals. If no response is observed after 10 mg of naloxone hydrochloride have been administered, the diagnosis of narcotic induced or partial narcotic induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available.
Postoperative Narcotic Depression: For the partial reversal of narcotic depression following the use of narcotics during surgery, smaller doses of naloxone hydrochloride are usually sufficient. The dose of naloxone hydrochloride should be titrated according to the patient's response. For the initial reversal of respiratory depression, Naloxone Hydrochloride Injection should be injected in increments of 0.1 to 0.2 mg intravenously at two- to three- minute intervals to the desired degree of reversal, i.e., adequate ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of naloxone hydrochloride may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress.
Repeat doses of naloxone hydrochloride may be required within one- to two-hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of narcotic. Supplemental intramuscular doses have been shown to produce a longer lasting effect.
Usage in Children
Narcotic Overdose-Known or Suspected: The usual initial dose in children is 0.01 mg/kg body weight given intravenously. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an intravenous route of administration is not available, Naloxone Hydrochloride Injection may be administered intramuscularly or subcutaneously in divided doses. If necessary, Naloxone Hydrochloride Injection can be diluted with Sterile Water for Injection.
Postoperative Narcotic Depression: Follow the recommendations and cautions under Usage in Adults - Postoperative Narcotic Depression (above). For the initial reversal of respiratory depression, naloxone hydrochloride should be injected in increments of 0.005 mg to 0.01 mg intravenously at two- to three-minute intervals to the desired degree of reversal.
Usage in Neonates
When using naloxone hydrochloride injection in neonates, a product containing 0.02 mg/mL should be used.
Narcotic-Induced Depression: The usual initial dose is 0.01 mg/kg body weight administered intravenously, intramuscularly or subcutaneously. This dose may be repeated in accordance with adult administration guidelines for postoperative narcotic depression.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
HOW SUPPLIED
Naloxone Hydrochloride Injection is available in the following packages:
0.4 mg/mL
1 mL DOSETTE® ampuls packaged in 10s (NDC 0641-1451-33)
1 mL DOSETTE® vials packaged in 10s (NDC 0641-0442-23)
10 mL Multiple Dose vials packaged individually (NDC 0641-2521-41)
STORAGE
Protect from light Store at controlled room temperature 15°- 30° C ( 59°- 86° F).
SIDE EFFECTS
Abrupt reversal of narcotic depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures and cardiac arrest In postoperative patients, larger than necessary dosage of naloxone hydrochloride may result in significant reversal of analgesia and in excitement
Hypotension, hypertension, ventricular tachycardia and fibrillation, and pulmonary edema have been associated with the use of naloxone hydrochloride postoperatively (see PRECAUTIONS and DOSAGE AND ADMINISTRATION: Usage in Adults - Postoperative Narcotic Depression).
DRUG INTERACTIONS
No information provided.
WARNINGS
Naloxone Hydrochloride Injection should be administered cautiously to persons including newborns of mothers who are known or suspected to be physically dependent on oploids. In such cases, an abrupt and complete reversal of narcotic effects may precipitate an acute abstinence syndrome.
The patient who has satisfactorily responded to naloxone should be kept under continued surveillance and repeated doses should be administered, as necessary, since the duration of action of some narcotics may exceed that of naloxone.
Naloxone is not effective against respiratory depression due to non-opiold drugs. Reversal of buprenorphine-induced respiratory depression may be incomplete. If an incomplete response occurs, respirations should be mechanically assisted.
PRECAUTIONS
In addition to Naloxone Hydrochloride Injection, other resuscitative measures, such as maintenance of a free airway, artificial ventilation, cardiac massage and vasopressor agents should be available and employed, when necessary, to counteract acute narcotic poisoning.
Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, and pulmonary edema have been reported. These have occurred in postoperative patients most of whom had pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, Naloxone Hydrochloride Injection should be used with caution in patients with pre-existing cardiac disease or patients who have received potentially cardiotoxic drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and mutagenicity studies have not been performed with naloxone hydrochloride. Reproductive studies in mice and rats demonstrated no impairment of fertility.
Pregnancy
Teratogenlc Effects - Pregnancy Category B. Reproduction studies have been performed in mice and rats at doses up to 1000 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to naloxone hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Naloxone Hydrochloride Injection is administered to a nursing woman.
OVERDOSE
There is no clinical experience with naloxone hydrochloride overdosage in humans.
In the mouse and rat, the intravenous LD50 is 150 ± 5 mg/kg and 109 ± 4 mg/kg, respectively. In acute subcutaneous toxicity studies in newborn rats, the LD50 (95% CL) is 260 (228-296) mg/kg. Subcutaneous injection of 100 mg/kg/day in rats for 3 weeks produced only transient salivation and partial ptosis following injection; no toxic effects were seen at 10 mg/kg/day for 3 weeks.
CONTRAINDICATIONS
Naloxone Hydrochloride Injection is contraindicated in patients known to be hypersensitive to it.
CLINICAL PHARMACOLOGY
Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.
Naloxone hydrochloride is an essentially pure narcotic antagonist, i.e., it does not possess the "agonistic" or morphinelike properties characteristic of other narcotic antagonists; naloxone hydrochloride does not produce respiratory depression, psychotomimetic effects or pupillary constriction. In the absence of narcotics or agonistic effects of other narcotic antagonists, it exhibits essentially no pharmacologic activity.
In the presence of physical dependence on narcotics, naloxone will produce withdrawal symptoms; it has not been shown to produce tolerance nor to cause physical or psychological dependence.
Mechanism of Action
While the mechanism of action of naloxone is not fully understood, the preponderance of evidence suggests that naloxone antagonizes the oploid effects by competing for the same receptor sites.
When Naloxone Hydrochloride Injection is administered intravenously, the onset of action is generally apparent within two minutes; the onset of action is only slightly less rapid when it is administered subcutaneously or intramuscularly. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than intravenous administration. The requirement for repeat doses of naloxone hydrochloride, however, will also be dependent upon the amount, type and route of administration of the narcotic being antagonized.
Following parenteral administration, naloxone hydrochloride is rapidly distributed in the body. It is metabolized in the liver, primarily by glucuronide conjugation and excreted in urine. In one study, the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ±12 minutes). In a neonatal study, the mean plasma half-life was observed to be 3.1 ± 0.5 hours.
PATIENT INFORMATION
See WARNINGS, PRECAUTIONS and CONTRAINDICATIONS.