Arsip untuk November, 2009

Penyakit Paru Obstruktif Menahun (PPOM)

Posted in Interna on 22 November 2009 by kadaverboy
DEFINISI
Penyakit Paru Obstruktif Menahun /PPOM (Chronic Obstructive Pulmonary Disease/COPD) adalah suatu penyumbatan menetap pada saluran pernafasan yang disebabkan oleh emfisema atau bronkitis kronis.

PPOM lebih sering menyerang laki-laki dan sering berakibat fatal.
PPOM juga lebih sering terjadi pada suatu keluarga, sehingga diduga ada faktor yang dirurunkan.

Bekerja di lingkungan yang tercemar oleh asap kimia atau debu yang tidak berbahaya, bisa meningkatkan resiko terjadinya PPOM. Tetapi kebiasaan merokok pengaruhnya lebih besar dibandingkan dengan pekerjaan seseorang, dimana sekitar 10-15% perokok menderita PPOM.

Angka kematian karena emfisema dan bronkitis kronis pada perokok sigaret lebih tinggi dibandingkan dengan angka kematian karena PPOM pada bukan perokok.
Sejalan dengan pertambahan usia, perokok sigaret akan mengalami penurunan fungsi paru-paru yang lebih cepat daripada bukan perokok. Semakin banyak sigaret yang dihisap, semakin besar kemungkinan terjadinya penurunan fungsi paru-paru.

PENYEBAB
Ada 2 (dua) penyebab dari penyumbatan aliran udara pada penyakit ini, yaitu emfisema dan bronkitis kronis.

Emfisema adalah suatu pelebaran kantung udara kecil (alveoli) di paru-paru, yang disertai dengan kerusakan pada dindingnya.
Dalam keadaan normal, sekumpulan alveoli yang berhubungan ke saluran nafas kecil (bronkioli), membentuk struktur yang kuat dan menjaga saluran pernafasan tetap terbuka. Pada emfisema, dinding alveoli mengalami kerusakan, sehingga bronkioli kehilangan struktur penyangganya. Dengan demikian, pada saat udara dikeluarkan, bronkioli akan mengkerut. Struktur saluran udara menyempit dan sifatnya menetap.

Bronkitis kronis adalah batuk menahun yang menetap, yang disertai dengan pembentukan dahak dan bukan merupakan akibat dari penyebab yang secara medis diketahui (misalnya kanker paru-paru). Pada saluran udara kecil terjadi pembentukan jaringan parut, pembengkakan lapisan, penyumbatan parsial oleh lendir dan kejang pada otot polosnya. Penyempitan ini bersifat sementara.

Adanya bahan-bahan iritan menyebabkan peradangan pada alveoli. Jika suatu peradangan berlangsung lama, bisa terjadi kerusakan yang menetap.
Pada alveoli yang meradang, akan terkumpul sel-sel darah putih yang akan menghasilkan enzim-enzim (terutama neutrofil elastase), yang akan merusak jaringan penghubung di dalam dinding alveoli.
Merokok akan mengakibatkan kerusakan lebih lanjut pada pertahanan paru-paru, yaitu dengan cara merusak sel-sel seperti rambut (silia) yang secara normal membawa lendir ke mulut dan membantu mengeluarkan bahan-bahan beracun.

Tubuh menghasilkan protein alfa-1-antitripsin, yang memegang peranan penting dalam mencegah kerusakan alveoli oleh neutrofil estalase.
Ada suatu penyakit keturunan yang sangat jarang terjadi, dimana seseorang tidak memiliki atau hanya memiliki sedikit alfa-1-antitripsin, sehingga emfisema terjadi pada awal usia pertengahan (terutama pada perokok).

GEJALA
Gejala-gejala awal dari PPOM, yang bisa muncul setelah 5-10 tahun merokok, adalah batuk dan adanya lendir.
Batuk biasanya ringan dan sering disalah-artikan sebagai batuk normal perokok, walaupun sebetulnya tidak normal.

Sering terjadi nyeri kepala dan pilek. Selama pilek, dahak menjadi kuning atau hijau karena adanya nanah.
Lama-lama gejala tersebut akan semakin sering dirasakan. Bisa juga disertai mengi/bengek.

Pada umur sekitar 60 tahun, sering timbul sesak nafas waktu bekerja dan bertambah parah secara perlahan. Akhirnya sesak nafas akan dirasakan pada saat melakukan kegiatan rutin sehari-hari, seperti di kamar mandi, mencuci baju, berpakaian dan menyiapkan makanan.
Sepertiga penderita mengalami penurunan berat badan, karena setelah selesai makan mereka sering mengalami sesak yang berat sehingga penderita menjadi malas makan.

Pembengkakan pada kaki sering terjadi karena adanya gagal jantung.
Pada stadium akhir dari penyakit, sesak nafas yang berat timbul bahkan pada saat istirahat, yang merupakan petunjuk adanya kegagalan pernafasan akut.

DIAGNOSA
Pada PPOM yang ringan, mungkin tidak ditemukan kelainan selama pemeriksaan fisik, kecuali terdengarnya beberapa mengi pada pemeriksaan dengan menggunakan <>I>stetoskop. Suara pernafasan pada stetoskop juga terdengar lebih keras.
Biasanya foto dada juga normal.

Untuk menunjukkan adanya sumbatan aliran udara dan untuk menegakkan diagnosis, dilakukan pengukuran volume penghembusan nafas dalam 1 detik dengan menggunakan spirometri.
Pada penderita PPOM akan terjadi penurunan aliran udara selama penghembusan nafas.

Jika PPOM terjadi pada usia muda, dicurigai adanya kekurangan alfa-1-antitripsin, sehingga perlu dilakukan pemeriksaan darah untuk mengetahui kadar afa-1-antitripsin dalam darah.

Spirometri

PENGOBATAN
Karena merokok sigaret merupakan penyebab paling penting dari PPOM, maka pengobatan utama adalah berhenti merokok. Menghentikan kebiasaan merokok pada saat penyumbatan airan udara masih ringan atau sedang, akan memperlambat timbulnya sesak nafas. Tetapi, berhenti merokok pada stadium manapun dari penyakit ini, pasti akan memberikan banyak keuntungan.
Penderita juga harus mencoba untuk menghindari pemaparan terhadap bahan iritan lainnnya di udara.

Unsur-unsur dari penyumbatan aliran udara yang bisa diperbaiki adalah kejang otot, peradangan dan peningkatan jumlah lendir. Perbaikan dari unsur-unsur tersebut akan mengurangi gejala-gejala.
Kejang otot bisa dikurangi dengan memberikan bronkodilator, termasuk agonis reseptor beta-adrenergik (albuterol inhaler) dan theophylline per-oral (melalui mulut) yang diserap lambat.
Peradangan bisa dikurangi dengan memberikan corticosteroid, tetapi hanya 20% penderita yang memberikan respon terhadap corticosteroid.
Tidak ada pengobatan terpercaya yang dapat mengurangi kekentalan lendir sehingga mudah dikeluarkan melalui batuk. Tetapi menghindari dehidrasi bisa mencegah pengentalan lendir. Minum cairan yang cukup untuk menjaga air kemih tetap encer dan bening. Pada PPOM yang berat, terapi pernafasan bisa membantu menghilangkan lendir di dada.

Terapi oksigen jangka panjang akan memperpanjang hidup penderita PPOM yang berat dan penderita dengan kadar oksigen darah yang sangat rendah.
Oksigen diberikan 12 jam/hari. Hal ini akan mengurangi kelebihan sel darah merah yang disebabkan menurunnya kadar oksigen dalam darah, memperbaiki fungsi mental dan memperbaiki gagal jantung akibat PPOM.
Terapi oksigen juga bisa memperbaiki sesak nafas selama beraktivitas.

Program latihan bisa dilakukan di rumah. Program ini bisa meningkatkan kualitas hidup dan kemandirian penderita, menurunkan frekuensi dan lamanya perawatan di rumah sakit dan meningkatkan kemampuan berlatih meskipun fungsi paru-parunya belum pulih sempurna.
Untuk melatih kaki bisa dilakukan latihan sepeda statis, naik-turun tangga dan berjalan.
Untuk melatih lengan bisa dilakukan latihan angkat beban.

Untuk penderita dengan kekurangan alfa-1-antitripsin yang berat, bisa diberikan protein pengganti melalui pemberian protein melalui infus setiap minggu.
Pencangkokan paru-paru bisa dilakukan pada penderita dibawah usia 50 tahun.

Pada penderita dengan emfisema yang berat, bisa dilakukan pembedahan yang disebut operasi reduksi volume paru-paru. Prosedurnya rumit dan penderita harus berhenti merokok setidaknya 6 bulan sebelum pembedahan dan menjalani program latihan intensif.
Pembedahan akan memperbaiki fungsi paru-paru dan kemampuan berlatih.

PROGNOSIS

30% penderita PPOM dengan sumbatan yang berat akan meninggal dalam waktu 1 tahun, dan 95% meninggal dalam waktu 10 tahun.
Kematian bisa disebabkan oleh kegagalan pernafasan, pneumonia, pneumotoraks (masuknya udara ke dalam rongga paru), aritmia jantung atau emboli paru (penyumbatan arteri yang menuju ke paru-paru).
Penderita PPOM juga memiliki resiko tinggi terhadap terjadinya kanker paru.

PENCEGAHAN
Jika penderita mengalami influenza atau pneumonia, PPOM akan semakin memburuk dengan jelas. Karena itu, penderita PPOM harus mendapatkan vaksinasi influenza setiap tahun dan vaksinasi pneumokokus setiap 6 tahun atau lebih.

Ectopic Pregnancy 2

Posted in Obgyn on 22 November 2009 by kadaverboy


TREATMENT FOR ECTOPIC PREGNANCY (Ectopic Pregnancy 2)

Medical Management

Methotrexate therapy of ectopic pregnancy has been used successfully over the last 2 decades. The folic acid antagonist, methotrexate, inhibits de novo synthesis of purines and pyrimidines, interfering with DNA synthesis and cell multiplication. Rapidly proliferating trophoblasts are very dependent on folic acid and thus differentially vulnerable to the cytotoxic effect of methotrexate, and this differential sensitivity forms the basis of the therapy. When methotrexate is administered to pregnant women undergoing planned termination, a single dose of 50 mg/m2 significantly blunts the β-hCG increment over the following 7 days and has been associated with a drop in circulating progesterone and 17-α-hydroxyprogesterone concentrations prior to abortion. It appears that methotrexate directly impairs trophoblastic production of hCG with a secondary decrement of corpus luteum progestin secretion. Hemodynamically stable patients with unruptured ectopic pregnancy measuring less than or equal to 4 cm by ultrasonography are eligible for methotrexate therapy. Patients with larger masses or evidence of acute intra-abdominal bleeding should undergo immediate surgical treatment. Methotrexate treatment regimens are shown in Table 2 and include the multiple dose, single dose, and the newly introduced two-dose protocol.

TABLE 2 Comparison of Methotrexate Regimens
Single-Dose Regimen Multiple-Dose Regimen Two-Dose Regimen
Methotrexate dose 50 mg/m2 1 mg/kg 50 mg/m2
Leucovorin dose NONE 0.1 mg/kg NONE
Dose frequency Day 0
Potential dose on day 7
Alternating-day dosing of methotrexate and leucovorin, maximum of four doses of each Day 0 and day 4
Potential doses on day 7 and day 11
β-hCG monitoring Day 0, day 4, day 7
Day 11 and day 14 if additional doses given
Day 0, and then odd-numbered days until success Day 0, day 4, day 7
Day 11 and day 14 if additional doses given
Success determined by 15% drop in β-hCG day 4 to day 7
15% drop in β-hCG day 11 to day 14 if second dose given
15% drop in β-hCG between any two blood draws 15% drop in β-hCG day 4 to day 7
15% drop in hCG day 7 to day 11 or day 11 to day 14 if third and fourth dose given

Multiple-Dose Methotrexate

Multiple-dose methotrexate therapy is tailored to the patient’s weight and ectopic pregnancy responsiveness. Outcomes of 12 studies comparing multiple-dose systemic methotrexate with laparoscopic salpingostomy are presented in Table 3. Between 1982 and 1997, this tabulation shows 338 cases of ectopic pregnancy treated with variable-dose methotrexate (number of medication administrations varies according to response). Of these cases, 93% were treated successfully with multiple-dose systemic methotrexate (no subsequent therapy was required), and 75% of the women tested had patent fallopian tubes; in addition, of the women desiring pregnancy, 58% had a subsequent intrauterine pregnancy and 7% developed a repeat ectopic pregnancy. These rates all compare favorably with conservative surgical management.

There is one randomized clinical trial comparing laparoscopic salpingostomy with systemic multiple dose methotrexate. In it, 100 patients with laparoscopy-confirmed ectopic pregnancy were randomly treated with systemic methotrexate or laparoscopic salpingostomy. In the 51 patients treated with methotrexate, seven (14%) required surgical intervention for active bleeding or tubal rupture. An additional course of methotrexate was required in two patients (4%) for persistent trophoblast, based on continued β-hCG secretion. Of the 49 patients in the salpingostomy group, four patients (8%) failed and required salpingectomies, and ten patients (20%) required treatment with methotrexate for persistent trophoblast. Homolateral tubal patency was present in 23/42 (55%) of the patients assessed in the methotrexate group and in 23/39 (59%) of those assessed in the salpingostomy group. This randomized study and previous meta-analysis have demonstrated the effectiveness of systemic methotrexate therapy as equal to laparoscopic salpingostomy.

TABLE 3 Outcome of Different Treatments for Ectopic Pregnancy
Subsequent Fertility Rate
Method Number of Studiesa Number of Patients Number with Successful Resolution Tubal Patency Rate Intrauterine Pregnancy Ectopic Pregnancy
Conservative laparoscopic surgery 32 1,626 1,516 (93%) 170/223 (76%) 366/647 (57%) 87/647 (13%)
Variable-dose methotrexate 12 338 314 (93%) 136/182 (75%) 55/95 (58%) 7/95 (7%)
Single-dose methotrexate 7 393 340 (87%) 61/75 (81%) 39/64 (61%) 5/64 (8%)
Direct-injection methotrexate 21 660 502 (76%) 130/162 (80%) 87/152 (57%) 9/152 (6%)
Expectant management 14 628 425 (68%) 60/79 (76%) 12/14 (86%) 1/14 (7%)
aReferences available on the Lancet Web site (http://www.thelancet.com) or from the journal’s London office. Accessed December 6, 2002.
From Pisarska MD, Carson SA, Buster JE, et al. Ectopic pregnancy. Lancet 1998;351:1115-1120.

Single-Dose Methotrexate

Single-dose methotrexate, although more convenient, is not as efficacious as multiple-dose methotrexate. The high success rates in the initial studies using single-dose methotrexate were most likely due to the inclusion of spontaneously aborting intrauterine pregnancies. Subsequent studies of single-dose methotrexate therapy involving 393 patients are presented in Table 3. Although overall success of treatment, measured as no surgical intervention, is 87%, 8% of patients required more than one dose of methotrexate. Of the patients considered successfully treated (with one or more doses), tubal patency was found in 81% of the women evaluated. The subsequent intrauterine pregnancy rate was 61%, and for ectopic pregnancies 8%, in the patients desiring future fertility in the same group (those treated with either one or more doses of methotrexate). Based on the clinical evidence presently available, the routine use of methotrexate as a single-dose intramuscular regimen is probably not as effective as multiple doses. However, single-dose therapy remains a standard according to publications of the American College of Obstetricians and Gynecologists.

With this background, a recent meta-analysis of 26 studies evaluating methotrexate dosing for ectopic pregnancy by Barnhart and colleagues showed an odds ratio of 1.96 higher likelihood of rupture with use of single-dose methotrexate over multidose therapy. Controlling for initial β-hCG value and the presence of cardiac activity, the failure rate with single-dose therapy was almost five times greater (odds ratio 4.75). What makes direct comparisons of these protocols even harder is that based on the data from this meta-analysis, 15% of patients under a single-dose protocol actually receive more than one dose, while 10%, 23%, and 14% of those under a multidose protocol actually need only 1, 2, or 3 doses of methotrexate, respectively.

Two-Dose Methotrexate Protocol

In recognition that the single-dose protocol has fewer visits and fewer injections but may have a higher failure rate, a two-dose protocol was introduced. This protocol uses the dosing and monitoring parameters of the single-dose protocol but gives a second dose of 50 mg/m2 on day 4, when only a serum β-hCG would have been drawn according to the single-dose protocol. No leucovorin rescue is used in this protocol. The same logic is used to determine if more methotrexate is needed based on the difference between the serum β-hCG on day 4 and day 7. In the single-dose protocol, a second dose would be given on day 7 if the β-hCG did not decline by at least 15% between day 4 and day 7 (Table 2). In the two-dose protocol, a second dose is given on day 4, and a third dose can be given on day 7 if the β-hCG did not decline by a least 15% between days 4 and 7. Thus, the two-dose protocol gives two doses in the first week and has provisions to give up to two more. In this way, the number of visits and surveillance laboratories are the same as the single dose, but more methotrexate is given sooner in hopes of maximizing success rate (without increasing complexity or the number of visits). This regimen was demonstrated to be safe in a three-center trial; the overall success rate will be determined as it is used more widely.

TABLE 4 Treatment with Multiple-dose Methotrexate
Indications for systemic methotrexate for uncomplicated ectopic pregnancy:

  • No rupture (hemodynamic stability)
  • UTZ size >4 cm
  • Β-hCG >10,000 mIU/mL
  • Positive fetal heartbeat: proceed with caution
  • Willingness of patient to comply with subsequent treatment monitoring
UTZ, ultrasound; hCG, human chorionic gonadotropin.

Safeguards and Counseling

Prior to instituting methotrexate therapy, physicians should evaluate baseline laboratory values. The patient should be screened with a complete blood count, liver function tests, and serum creatinine. A chest x-ray should be considered in women reporting a history of prior pulmonary disease due to their risk of developing methotrexate-related interstitial pneumonitis.

During methotrexate therapy, a woman should be examined by a single examiner only once, to diminish the risk of causing mechanical trauma and tubal rupture. The physician and the patient must recognize that transient pain (“separating” or “tearing pain”) is common. Transient pelvic pain from tubal bleeding or hematoma formation at the ectopic site frequently occurs 3 to 7 days after the start of therapy, lasts 4 to 12 hours, and is presumably due to tubal abortion. Perhaps the most difficult aspect of methotrexate therapy is learning to distinguish the transient abdominal pain of successful therapy from that of a rupturing ectopic pregnancy. Physicians must therefore carefully observe for clinical indications that an operation is necessary (Tables 4, 5). Thus, surgical intervention is required when pain is worsening and persistent beyond 12 hours. Orthostatic hypotension or a falling hematocrit should lead to immediate surgery. Sometimes, it is necessary to hospitalize the patient with pain for observation (usually about 24 hours) to insure a correct diagnosis. In addition, colicky abdominal pain is common during the first 2 or 3 days of methotrexate therapy, and the woman should avoid gas-producing foods such as leeks and cabbage. Women receiving methotrexate should discontinue prenatal vitamins, as they contain folic acid, and should especially avoid any additional folic acid supplementation. Finally, the patient should avoid exposure to the sun because photosensitivity can be a complication of methotrexate.

TABLE 5 Dealing with Methotrexate Failure
Operate when high suspicion of rupture:

  • Pain is severe and persistent, regardless of β-hCG levels
  • Falling hematocrit
  • Orthostatic hypotension
Consider operating when signs of treatment failure:

  • Levels of β-hCG do not decline by at least 15% between days 4 and 7 of treatment
  • Levels of β-hCG increase or plateau after first week of treatment

Methotrexate by Direct Injection

In 1987, Feichtinger and Kemeter instilled 10 mg (1 mL) of methotrexate into an ectopic gestational sac under transvaginal ultrasonography, and resolution occurred within 2 weeks. Direct injection delivers concentrations of methotrexate to the site of implantation at higher concentrations than those achieved with systemic administration. Less systemic distribution of the drug should decrease the overall toxicity. However, this approach has the substantial disadvantage of requiring laparoscopic or ultrasound needle guidance.

Outcomes in 21 studies involving direct injection of methotrexate with either laparoscopic or transvaginal ultrasound guidance are presented in Table 3. Between 1989 and 1997, 75.1% of 668 cases of ectopic pregnancy were treated successfully with methotrexate by direct injection, and some patients required more than one injection. Tubal patency and subsequent pregnancy rates were comparable to conservative laparoscopic surgery and systemic methotrexate: 80.2% of the women tested had patent oviducts, and of the women desiring pregnancy, 57.2% had a subsequent intrauterine pregnancy and 5.9% developed a recurrent ectopic pregnancy.

Randomized, controlled trials have demonstrated successful treatment with methotrexate by direct injection in 86.2% of the patients. Again, successful therapy included some patients who received more than one injection. Tubal patency was present in 85.1% of the women evaluated, and intrauterine pregnancy occurred in 73.1% of the women desiring subsequent fertility. One of the earlier randomized, controlled trials was discontinued because three of seven patients assigned to laparoscopic injection of methotrexate required additional laparoscopic surgery. Even with the higher success rate in the randomized trials, this technique is more cumbersome than systemic methotrexate. Given the overall tolerability and high success rate of systemic methotrexate, it continues to be the most accepted nonsurgical treatment modality.

Side Effects

High doses of methotrexate can cause bone marrow suppression, hepatotoxicity, stomatitis, pulmonary fibrosis, alopecia, and photosensitivity. These side effects are infrequent in the short treatment schedules used in ectopic pregnancy and can be attenuated by the administration of leucovorin (citrovorum factor). The side effects of methotrexate resolve within 3 to 4 days after the therapy is discontinued. Impaired liver function is the most common side effect. Other side effects include stomatitis, gastritis and enteritis, and bone marrow suppression. Local therapy by direct injection of methotrexate into the ectopic gestation resulted in fewer side effects, likely because of less systemic absorption. Even with local injection, impaired liver function tests, gastritis and enteritis, and bone marrow suppression can occur. Additional case reports exist in the literature. Cases of life-threatening neutropenia and febrile morbidity can occur after single or multidose intramuscular methotrexate, requiring hospitalization. Cases of transient interstitial pneumonitis from methotrexate therapy for ectopic pregnancy have been observed. Reversible alopecia (a loss of 33% to 50% of the scalp hair) on two separate occasions following single-dose therapy for an ectopic pregnancy has also been reported. Rarely, hematosalpinx and pelvic hematoceles have been noted as late sequelae of methotrexate following the normalization of β-hCG levels. These patients have pelvic pain, abnormal bleeding, and a pelvic mass, requiring surgical intervention, 3 to 5 months after therapy.

Fortunately, the side effects reported with methotrexate used to treat ectopic pregnancy have mostly been minor. Out of 100 patients treated in one study, only two patients developed stomatitis and three had transient elevation of transaminases, all resolving spontaneously. Another study that used the single-dose regimen had only one patient reporting nausea and vomiting following methotrexate treatment. Thus, with its overall good tolerability, methotrexate remains the first choice before surgical therapy.

Direct Injection of Cytotoxic Agents

Prostaglandins, hyperosmolar glucose, potassium chloride, and saline by direct injection have been tried as therapeutic alternatives to methotrexate. The limited experience with these agents, poor success rates, and the need for laparoscopic or transvaginal aspiration makes these unattractive treatment alternatives.

Evidence-Based Recommendation

Multiple-dose systemic methotrexate is the first-line medical treatment for ectopic pregnancy. Nearly half of patients under a multidose protocol will require fewer doses for ectopic pregnancy resolution. (Strength of recommendation: A.)

Surgical Treatment

Since the first successful salpingectomy (resection of involved fallopian tube segment with implanted trophoblastic tissue) performed by Tait in 1884, ectopic pregnancies traditionally have been treated by salpingectomy, usually by laparotomy. Historically, ectopic pregnancies were diagnosed at the time of emergency surgery, when concern for the patient’s life superseded any concerns for her future fertility. It was not until 1953, when Stromme performed the first conservative procedure (salpingostomy, or removal of only the ectopic pregnancy with conservation of the tube) for ectopic pregnancy, that subsequent successful pregnancy outcomes were reported, confirming the potential for fertility preservation after salpingostomy. These surgical techniques have been modified for endoscopy. The laparoscopic approach is associated with less blood loss, less analgesia requirement, and a shorter duration of hospital stay. In addition, cost analysis has demonstrated significant savings in randomized trials. When evaluating subsequent fertility, intrauterine pregnancy rates are comparable for laparoscopy and laparotomy, as are rates of recurrent ectopic pregnancy.

Ruptured Ectopic Pregnancy

Early diagnosis and treatment of ectopic pregnancy avoids rupture in most cases. In the 1970s, 13.5% to 17.8% of patients with ectopic pregnancies arrived for treatment in hypovolemic shock, whereas in the early 1980s, only 4.4% of patients arrived in this condition. Today, either laparotomy or laparoscopy with salpingectomy is the first choice for rupture.

Once contraindicated over concern of decreased venous return from intraperitoneal insufflation, laparoscopic salpingectomy can be successful in patients in hypovolemic shock. Still, in critical instances when expeditious entry into the peritoneal cavity and tamponade of bleeding is necessary, rapid laparotomy to stem the bleeding is the preferred method. Nearly all patients in hypovolemic shock require blood transfusions; those with large red blood cell requirements also need fresh frozen plasma. In the hands of a highly skilled laparoscopist, with adequate cardiac monitoring and anesthesia, laparoscopic salpingectomy is an acceptable alternative to laparotomy even when there has been extensive intraperitoneal bleeding. At present, it is the surgeon’s choice of laparoscopy or laparotomy for ruptured ectopic pregnancy.

Stable Ectopic Pregnancy

If methotrexate is contraindicated, laparoscopic salpingostomy is the first surgical choice. Alternatively, salpingectomy can be performed either during laparotomy or laparoscopy by using cautery or sutures (laparoscopic or endoloops). A review of data from nine studies showed that subsequent to salpingostomy, 53% of patients have intrauterine pregnancies compared with 49.3% after salpingectomy. Recurrent ectopic pregnancy rates were slightly higher after conservative surgery, 14.8% compared with 9.9%. Other studies have suggested a higher intrauterine pregnancy rate in women after salpingostomy, but at the cost of a possible higher risk of recurrent ectopic after 3 years of follow-up. Laparoscopic salpingectomy is preferred over salpingostomy in cases of uncontrollable bleeding not resolving with conservative measures when extensive tubal damage is present, if the ectopic pregnancy has recurred in the same tube, if it is a large pregnancy (>5 cm), and if sterilization is desired.

The recommended conservative surgical procedure for an ampullary ectopic pregnancy is linear salpingostomy, because the ectopic nidation typically is located between the endosalpinx and serosa rather than in the tubal lumen. A linear salpingostomy is created through a longitudinal incision by electrocautery, scissors, or laser over the bulging antimesenteric border of the fallopian tube. The products of conception are removed with forceps or gentle flushing or suction. After maintaining hemostasis, the incision is left to heal by secondary intention or closed primarily. There appears to be no additional benefit to suturing the tubal defect closed, as studies have shown no difference in subsequent tubal patency rates, postoperative adhesion rates, or cumulative pregnancy rates.

Historically, isthmic segment pregnancies were routinely treated with segmental excision followed by intraoperative or delayed microsurgical anastomosis. The tubal lumen is narrower and the muscularis is thicker in the isthmus than in the ampulla, predisposing the isthmus to greater damage after salpingostomy and greater rates of proximal tubal obstruction. With today’s high success rates of in vitro fertilization (IVF), tubal anastomosis is rarely performed and the resected tubal segment is bypassed altogether by use of ART. Manual fimbrial expression, also known as milking, should not be used unless the trophoblastic tissue is already aborting spontaneously through the fimbriae.

Laparoscopic salpingostomy and fimbrial expression have been evaluated in 32 studies and are presented in Table 3. Of the 1,626 patients treated between 1980 and 1997, treatment was successful in 93.4% (defined as requiring no additional therapy). Of the patients evaluated for tubal patency by using either hysterosalpingography or laparoscopy, 76% had patent tubes. Of the women desiring subsequent fertility, 56.6% had an intrauterine pregnancy and 13.4% developed another ectopic pregnancy.

Persistent Ectopic Pregnancy Following Salpingostomy

Persistent ectopic pregnancy is diagnosed by a plateauing or rising β-hCG concentration following conservative surgical therapy. The β-hCG level should be checked on postoperative day 1, keeping in mind that a drop of <50%>

The increased rate of persistent ectopic pregnancies has been a criticism of conservative laparoscopic therapy when compared with laparotomy. A decision analysis that compared prophylactic methotrexate with linear salpingostomy against no methotrexate in a group of 1,000 women concluded that prophylactic methotrexate at the time of surgery was preferable if certain clinical conditions are met as follows: (a) the incidence of persistent ectopic pregnancy is greater than 9% with observation alone after salpingostomy, (b) the incidence of persistence is less than 5% when prophylactic methotrexate is given, (c) the probability of ectopic pregnancy rupture is greater than 7.3% with a persistent ectopic pregnancy, and (d) the complication rate associated with prophylactic methotrexate is less than 18%. Because the great majority of clinical circumstances meet these recommendations, prophylactic methotrexate administration is recommended.

Evidence-Based Recommendation

Due to lower morbidity and equal efficacy, laparoscopic surgery is preferable to laparotomy in the treatment of bleeding or complicated ectopic pregnancy. Salpingectomy by laparotomy is reserved for ectopic ruptures with a hemodynamically unstable patient. (Strength of recommendation: A.)

Ectopic Pregnancy and Assisted Reproductive Technology

Incidence

The risk of ectopic pregnancy is increased in patients undergoing an ART procedure. This increased risk has been attributed to the cause of infertility for which most patients seek treatment, that is, tubal factor infertility. Information on ectopic pregnancies resulting from ART comes from data obtained from institutions in the United States and Canada reporting to the Society for Assisted Reproductive Technology. The rate of pregnancies that resulted in ectopic pregnancies after IVF in 1999 was 3%, with newer figures from 2004 reporting the ectopic rate to be about 2%. The latter included outcome of ART cycles using fresh, nondonor eggs or embryos in approximately 76,000 embryo transfers. This lower percentage likely reflected the trend toward performing salpingectomies when hydrosalpinges are present to improve the success of ART.

Location

As in naturally occurring ectopic pregnancies, the fallopian tube is the most common site for ectopic pregnancies following IVF. Data obtained from three case-control studies reveal that 82.2% of ectopic pregnancies were tubal. When tubal location was specified, 92.7% were ampullary and 7.3% interstitial. Extratubal ectopic nidations were as follows: 4.6% ovarian or abdominal, 1.5% cervical, and 11.7% heterotopic pregnancies (Fig. 1).

Tubal Pathology

Tubal pathology is the most important predisposing factor for ectopic pregnancy in patients undergoing IVF. Ectopic pregnancies are four times higher in patients with tubal factor infertility compared with patients with normal tubes. Hydrosalpinges are associated more commonly with ectopic pregnancy than other types of tubal pathology. Prior tubal reconstructive surgery (salpingostomy) increases the risk of ectopic pregnancy by 10% above that in patients with tubal factor infertility without prior surgery.

Thus, it is not surprising that patients with previous pelvic inflammatory disease have a sixfold increase in ectopic pregnancy after IVF. However, a history of prior ectopic pregnancy does not seem as important a risk factor in IVF cycles as in natural cycles.

Salpingectomy, particularly with hydrosalpinx, has been shown to decrease risks of ectopic pregnancy while increasing pregnancy rates after IVF. Meta-analysis has demonstrated that the presence of hydrosalpinges decreases the chance for viable pregnancy by approximately 50% when compared with patients with tubal disease but without hydrosalpinges. The implantation rate was also noted to be 50% lower with a higher chance of miscarriage and ectopic gestation. The ultimate conclusion is that when a hydrosalpinx is present, there is a decreased pregnancy rate with resultant decreased delivery rate following IVF. In addition, patients who undergo salpingectomy or proximal tubal occlusion prior to oocyte retrieval and transfer are at decreased risk for pelvic infection as well as future ectopic pregnancy.

Ovulation Induction

Hormone alterations during ovulation induction theoretically alter tubal function. In animal models, estrogen administration results in functional tubal blockage and embryo arrest in the fallopian tube. In humans, steroid hormones alter tubal function and contractility, thus affecting tubal peristalsis. There remains controversy as to whether ovulation-inducing agents, including clomiphene citrate, increase ectopic pregnancy rates, but it will be difficult to separate out the impact of the therapeutic agent from occult tubal disease.

Embryo Transfer

Knutzen and associates injected 40 µL of radiopaque fluid in mock embryo transfers and found that the material entered the tubes either partially or totally in 44% of subjects, suggesting that misplacement of embryos into the fallopian tubes leads to ectopic pregnancy. Embryo catheter placement also was implicated in the increased risk of ectopic pregnancies, which occurred more frequently in patients who underwent deep fundal transfer versus midcavity placement. Although transfer techniques may increase the chances of embryos reaching the fallopian tubes, it is the tubal pathology preventing the embryos from moving back into the uterus and resulting in an ectopic pregnancy.

Heterotopic Pregnancy

Heterotopic pregnancies occur in 1% to 3% of pregnancies following ART procedures and are usually diagnosed incidentally on routine follow-up ultrasonographic studies. This increased prevalence of heterotopic pregnancies following ART may be related to ovarian hyperstimulation and multiple ovum development. Of 111 reported heterotopic pregnancies following ART, 88.3% were tubal, 6.3% cornual, 2.7% abdominal, 1.8% cervical, and 0.9% ovarian.

Evidence-Based Recommendation

Heterotopic and extratubal ectopic pregnancies are more frequent following ART than with natural cycles. Salpingectomy or proximal tubal occlusion of a preexisting hydrosalpinx prior to IVF helps to prevent tubal ectopic pregnancies while increasing pregnancy rates following ART. (Strength of recommendation: B.)

Expectant Management

Ectopic pregnancies may resolve spontaneously. In a cavalier experiment in 1955, Lund hospitalized 119 women with ectopic pregnancy for observation. All were at least 6 weeks gestation. Some required multiple blood transfusions, and many were hemodynamically unstable. However, 68 resolved without surgery being required. Twelve additional studies reported in the literature since Lund’s study found similar results (Table 3). Of the ectopic pregnancies, 67.2% resolved without surgery. Thus, both conservative medical and surgical therapy overtreats at least 50% of women with ectopic pregnancy. Falling β-hCG levels under 1,000 mIU/mL have been followed with conservative expectant management. Although patients with an equivocal diagnosis of ectopic pregnancy may be treated in this fashion, there are no data to support expectant management in clinical practice. In addition, despite close follow-up and even in the context of declining β-hCG levels, tubal rupture may still occur.

Evidence-Based Recommendation

Expectant management of ectopic pregnancy may be considered an appropriate conservative therapy for some patients with low initial (1,000 mIU/mL) and falling β-hCG levels. Both clinicians and patients need to be aware of the potential risks of choosing expectant management over proven therapies.

Cost Analysis

The last estimated U.S. costs for ectopic pregnancy are over 15 years old. In 1990, total costs for ectopic pregnancies were estimated to be $1.1 billion. Direct costs, expenditures for health care, accounted for 77% of the total costs, and the remainder were incurred as a result of lost wages or household responsibilities not performed due to illness (indirect costs). Direct costs from hospital charges were estimated at $6,079 per case, with hospital accommodations (mean length of stay, 3.47 days) and operating room charges accounting for the majority of the hospital expense, 36% and 40%, respectively. An additional $3,254 for professional fees increased inpatient charges to $9,333, and $149 for postoperative follow-up visits increased the total direct cost to $9,482 per case. Indirect costs for a 28-day disability were estimated at $250.5 million, 67% as a result of lost wages and the remainder from lost household duties. These costs are likely substantially higher today.

European studies by Mol and colleagues have attempted to evaluate costs, but it is important to remember that they figured in longer hospital stays and more sick days than are customary in the United States and that the costs they estimated are within a socialized medical system. A study undertaken to compare the costs of systemic methotrexate with surgery concluded that there would be a reduction in overall costs if patients were treated without confirmatory laparoscopy when β-hCG levels were below 3,000 mIU/mL; otherwise, there was not a substantial cost saving over surgery. Because a confirmatory laparoscopy is no longer required for diagnosis, the lower cost for medical therapy is more realistic. Compared with the cost of a laparoscopic salpingostomy, methotrexate results in an estimated 20% decrease in the cost of treatment.

A decision analysis by Morlock and associates created a model to estimate the costs incurred by treating ectopic pregnancy by methotrexate or by laparoscopic salpingostomy. They felt that such an analysis was important because although previous studies found cost advantages with methotrexate, they had not adequately considered failure of ectopic resolution after only one dose of methotrexate or the potential side effects and complications of methotrexate use. They also felt that several European studies had calculated the costs of inpatient laparoscopy, not currently standard care in the United States where treatment is routinely done in the outpatient setting. Incorporating all of the assumptions about failed methotrexate treatment and costs of surgery and hospitalization for medical failures, the authors found a $3,011 cost saving with methotrexate treatment compared with laparoscopy. Even when they altered the model by assuming the lowest resolution rate for methotrexate-treated ectopic pregnancy of 57% and highest complication rates, the model still supported the use of methotrexate with a saving of $760.

Finally, it should be noted that Ailawadi and colleagues performed a decision analysis comparing the complicating rate and cost of diagnosis ectopic pregnancy with evaluation of the uterus prior to medical management versus presumptively treating women with a presumed ectopic pregnancy with methotrexate without confirming the diagnosis with a dilation and curettage (D&C). Surprisingly, the outcomes were quite similar. Thus, there is no advantage to taking the “shortcut”of treating women presumed to but not confirmed to have an ectopic pregnancy in terms of cost and/or complications. Data supporting the definitive diagnosis was that there were fewer visits required by patients after performance of an evacuation of the cavity, as fewer women needed medical management and evaluation of serial β-hCG concentration. Moreover, a more accurate prognosis can be given to a woman regarding recurrence of miscarriage, ectopic pregnancy, or overall fecundity if a miscarriage is accurately distinguished from an ectopic pregnancy.

Evidence-Based Recommendation

Systemic methotrexate for unruptured ectopic pregnancy is less expensive than surgery, and direct costs are decreased substantially with methotrexate therapy. In addition to its cost effectiveness, systemic methotrexate does not subject patients to the risks of surgery. This cost benefit, however, diminishes with higher β-hCG titers and even disappears with levels greater than 3,000 mIU/mL because of single-dose methotrexate treatment failures and increased complications. (Strength of recommendation: B.)

Rare Types of Ectopic Pregnancy

Abdominal Pregnancy

The incidence of abdominal pregnancy is estimated at 1 in 8,000 births and represents 1.4% of all ectopic pregnancies. The prognosis is poor, with an estimated maternal mortality rate of 5.1 per 1,000 cases. The risk of dying from an abdominal pregnancy is 7.7 times higher than from other forms of ectopic pregnancy. The high rate of morbidity and mortality from abdominal pregnancy often results from a delay in diagnosis.

Abdominal pregnancies can be categorized as primary or secondary. These ectopic pregnancies may become apparent anywhere throughout gestation, from the first trimester to fetal viability. Symptoms may vary from those considered normal for pregnancy to severe abdominal pain, intra-abdominal hemorrhage, and hemodynamic instability. Primary abdominal pregnancies are rare and are thought to occur as a result of primary peritoneal implantation. They usually abort early in the first trimester due to hemorrhagic disruption of the implantation site and hemoperitoneum. Secondary abdominal pregnancies occur with reimplantation after a partial tubal abortion or intraligamentary extension following tubal rupture. Historical criteria to distinguish between primary and secondary abdominal pregnancies are moot, because treatment is guided by the clinical picture.

Ultrasonography is the diagnostic tool of choice and usually can identify the empty uterus along with the extrauterine products of conception. If the fetus is near viability, hospitalization is recommended. If time permits, bowel preparation, administration of prophylactic antibiotics, and adequate blood replacement should be made available prior to an operative delivery. Unless the placenta is implanted on major vessels or vital structures, it should be removed. Although complications may occur, including sepsis, abscess formation, secondary hemorrhage, intestinal obstruction, wound dehiscence, amniotic fluid cyst formation, hypofibrinogenemia, and preeclampsia, the placenta can be left in place to prevent further hemorrhage at the time of surgery. In contrast to the typical tubal ectopic pregnancy, methotrexate is unlikely to accelerate retained placental absorption because the trophoblastic cells are no longer actively dividing.

Ovarian Pregnancy

Ovarian pregnancy, the most common form of abdominal pregnancy, is rare, accounting for less than 3% of all ectopic gestations. Clinical findings are similar to those of tubal ectopic gestations: abdominal pain, amenorrhea, and abnormal vaginal bleeding. In addition, hemodynamic instability as a result of rupture occurs in 30% of patients. Women with ovarian pregnancies are usually young and multiparous, but the factors leading to ovarian pregnancies are not clear.

The diagnosis usually is made by the pathologist because many ovarian pregnancies are mistaken for a ruptured corpus luteum or other ovarian tumors. Only 28% of cases were diagnosed correctly at time of laparotomy. The recommended treatment is cystectomy, wedge resection, or oophorectomy during laparotomy, although laparoscopic removal has been successful.

Cornual Pregnancy

Cornual or interstitial pregnancy accounts for 4.7% of ectopic gestations and carries a 2.2% maternal mortality. Clinically, a pregnancy implanted at this site where the fallopian tube is traversing the muscular wall of the uterus is seen as a swelling lateral to the round ligament. Almost all cases are diagnosed after the patient is symptomatic. The most frequent symptoms are menstrual aberration, abdominal pain, abnormal vaginal bleeding, and shock, resulting from the brisk hemorrhage associated with uterine rupture. Due to myometrial distensibility, rupture is usually delayed, occurring at 9 to 12 weeks gestation.

A unique risk factor for interstitial pregnancy is previous salpingectomy, present in about 25% of patients. Only a high index of suspicion and repeated ultrasonographic examination with Doppler flow studies allows early diagnosis. With a timely early diagnosis, alternatives to the traditional cornual resection during laparotomy have been performed successfully. These include laparoscopic cornual resection, systemic methotrexate administration, local injection of methotrexate, potassium chloride injection, and removal by hysteroscopy. Regardless of the initial treatment attempted, if uncontrolled hemorrhage occurs, immediate laparotomy with uterine repair or hysterectomy is warranted to stop the blood loss.

Cervical Pregnancy

The incidence of cervical pregnancy ranges from 1 in 2,500 to 1 in 12,422 pregnancies. The most common predisposing factor is a prior D&C, present in 68.6% of patients. Interestingly, 31% of these were performed for termination of pregnancy. Other predisposing factors implicated in cervical pregnancies are previous cesarean delivery and IVF.

The most common initial symptom of cervical pregnancy is painless vaginal bleeding. These extrauterine pregnancies are usually diagnosed incidentally during routine ultrasonography or at the time of surgery for a suspected abortion in progress. In reported cases, 91% of patients sought treatment for vaginal bleeding, and 29.2% had massive bleeding. Not surprisingly, abdominal pain occurred with vaginal bleeding in only 25.8% of cases. The cervix is usually enlarged, globular, or distended. On occasion, it appears cyanotic, hyperemic, and soft in consistency. Sonography and magnetic resonance imaging have improved diagnosis of cervical pregnancy. Up to 81.8% of patients have been diagnosed correctly with ultrasonographic identification of the gestational sac in the cervix below a closed internal cervical os, with trophoblastic invasion into the endocervical tissue.

When the patient is hemodynamically stable, conservative therapy commonly is employed. There are no large studies-only several case series for clinical guidance. These have shown that use of methotrexate, local prostaglanding or hyperosmolar glucose injection, curettage, or a combination of these methods have been successful. Prior to curettage, uterine artery embolization minimizes the substantial risk of postevacuation hemorrhage. Systemic and local treatment with various agents carries an overall success rate of 81.3%. Unfortunately, massive hemorrhage may occur despite conservative measures, and hysterectomy may be the only lifesaving option.

Heterotopic Pregnancy

Heterotopic pregnancy is the coexistence of an intrauterine and ectopic gestation. In 1948, the spontaneous heterotopic pregnancy rate was calculated as 1 in 30,000 pregnancies, based on an ectopic pregnancy incidence of 0.37% and dizygous twinning rate of 0.8%. In the 1980s, the calculation rose to 1 in 10,000 due to an increased ectopic pregnancy rate. Today, heterotopic pregnancies occur in 1 in 3,889 to 1 in 6,778 pregnancies in the general population. Out of almost 133,000 pregnancies reported in the U.S. ART Registry between 1999 and 2002, 207 heterotopic pregnancies were reported, an incidence of about 1:640. In a review of 66 heterotopic pregnancies by Reece and associates, 93.9% were tubal and 6.1% ovarian.

Simultaneous existence of intra- and extrauterine pregnancies poses several diagnostic pitfalls. Heterotopic pregnancies are diagnosed in most cases after clinical signs and symptoms develop, and 50% of patients are admitted for emergency surgery following rupture. The delay in diagnosis is secondary to the finding of an intrauterine pregnancy, which provides false reassurance of absence of pathology, with the assumption that any symptoms will be self-limited.

Similar to tubal ectopic pregnancies, the most common complaint is lower abdominal pain. Routine ultrasonography detects only about 50% of tubal heterotopic pregnancies, and the remainder are diagnosed during laparoscopy or laparotomy when patients become symptomatic. Serial levels of the β-hCG are not helpful due to the effect of the intrauterine pregnancy.

If patients are hemodynamically unstable, exploratory laparotomy is warranted. If the diagnosis is suspected or the patient is symptomatic but hemodynamically stable, laparoscopy can be performed. Expectant management is not recommended, because β-hCG levels cannot be monitored adequately and the course of the ectopic cannot be followed. Systemic methotrexate is contraindicated if a viable intrauterine pregnancy is present and desired. Local injection of methotrexate with potassium chloride has been noted as successful in a small case series.

Summary Points

  • In most circumstances, ectopic pregnancy can be diagnosed before symptoms develop and treated definitively with few complications.
  • Quantitative β-hCG testing, ultrasonography, and curettage allow early diagnosis of ectopic pregnancy and use of medical therapy as the initial therapy option.
  • Conservative surgical therapy and medical therapy for ectopic pregnancy are comparable in terms of success rates and subsequent fertility. Medical therapy is the preferred choice because of the freedom from surgical complications and lower cost.
  • Surgery is the treatment of choice for hemorrhage, medical failures, neglected cases, and when medical therapy is contraindicated.
  • Multiple-dose methotrexate is preferable to single-dose methotrexate, direct injection, or tubal cannulation and is the first choice for unruptured, uncomplicated ectopic pregnancy.
  • Laparoscopic salpingostomy or salpingectomy is favored for cases of intra-abdominal hemorrhage, medical failure, neglected cases, and complex cases when medical therapy is contraindicated.
  • Prophylactic postoperative systemic methotrexate (a single dose) can prevent virtually all cases of persistent ectopic pregnancy following salpingostomy.
  • Salpingectomy prior to IVF decreases ectopic pregnancy incidence while increasing pregnancy rates in select patients with preexisting tubal disease.

Ectopic Pregnancy (Part 1)

Posted in Obgyn on 22 November 2009 by kadaverboy

Beata E. Seeber
Kurt T. Barnhart
(Danforth’s Obstetrics and Gynecology, 10th Edition, Lippincott Williams & Wilkins.2008)

Ectopic pregnancy, the implantation of a fertilized ovum outside of the endometrial cavity, is a condition that is unique to primates. Although ectopic pregnancy remains a leading cause of life-threatening first-trimester morbidity, informed clinical suspicion and modern diagnostic procedures now routinely lead to diagnosis and treatment at the early signs of symptoms. Management of ectopic pregnancy has changed dramatically over the years. Medical therapy with systemic methotrexate, an intervention targeted specifically toward proliferating trophoblasts, is now often preferred to surgery as standard first-line treatment. However, surgery remains the first choice when rupture causes intraperitoneal hemorrhage, medical failures, neglected cases, and cases where medical therapy is contraindicated. In the wake of these changes, the United States has seen a considerable drop in maternal morbidity and mortality from this disease.

Early diagnosis and selection of optimal therapy are key to prevention of complications, preservation of fertility, control of costs, and elimination of mortality. The optimal dosing protocol for methotrexate therapy remains controversial. Similarly, the timing and technique for surgical intervention during medical failures are for the most part empirical. Using an evidence-based approach to the diagnosis of and treatment for ectopic pregnancy, this chapter provides a comprehensive examination of the standard of care for this serious gynecologic disease.

Incidence

The incidence of ectopic pregnancy in the United States is not known precisely. Recent attempts by the Centers for Disease Control and Prevention (CDC) to estimate the incidence of this disease have been thwarted, because there are no clear reporting standards and many cases are treated medically in outpatient facilities and are thus not recorded in hospital registries. The latest reported numbers date back to the mid 1990s. Where hospital records were used, a relentless increase in ectopic pregnancies from 4.5 per 1,000 in 1970 to 16.8 per 1,000 in 1989 to 19.7 per 1,000 (108,000 cases) in 1992 was reported. Several recent epidemiologic trends make it likely that the current incidence of ectopic pregnancy is even higher. First, there is a continued increase in the risk factors associated with ectopic pregnancy (Table 5.1). Second, there is increased ascertainment of ectopics from use of more sensitive and specific diagnostic methods that detect many cases that in the past may have resolved spontaneously without diagnosis or treatment (increase in prevalence due to lead-time bias). Third, with the increasing use of assisted reproductive technology (ART) for treatment of infertility, there is increased risk of ectopics, which comprise up to 5% of pregnancies achieved by using ART. Not surprisingly, heterotopics also are being reported with increasing frequency in ART pregnancies. Between 1979 and 1986, 13% of maternal deaths were secondary to ectopic pregnancy; by 1992, this dropped to 9%. However, ectopic pregnancies continue to be the leading cause of maternal death in the first trimester, accounting for 5% to 6% of all maternal deaths in the United States. Ninety percent of these deaths were due to hemorrhagic complications.

Pathogenesis

Any event that impairs the ability of the tube to transport gametes or embryos will predispose to ectopic implantation. The most common site of ectopic pregnancy is the fallopian tube, which accounts for 98.3% of all ectopic gestations. Of tubal implantation sites, the ampulla is observed in 79.6%, 12.3% are in the isthmus, 6.2% are in the fimbrial end, and the remaining 1.9% occur in the interstitial (cornual) region. Ectopic nidation outside the fallopian tubes is rare; only 1.4% of ectopic pregnancies are abdominal pregnancies, 0.15% ovarian, and 0.15% cervical (Fig. 5.1).

TABLE 5.1 Risk Factors Associated with Ectopic Pregnancy
Patients at increased risk need aggressive monitoring of their pregnancies immediately after first missed menses.
Risk Factor Odds Ratioa
High risk
Tubal surgery 21.0
Tubal ligation 9.3
Previous ectopic pregnancy 8.3
In utero exposure to DES 5.6
Use of IUD 4.2 – 45.0
Tubal pathology 3.8 – 21.0
Assisted reproduction 4.0
Moderate risk
Infertility 2.5 – 21.0
Previous genital infections 2.5 – 3.7
Multiple sexual partners 2.1
Salpingitis isthmica nodosa 1.5
Low risk
Previous pelvic infection 0.9 – 3.8
Cigarette smoking 2.3 – 2.5
Vaginal douching 1.1 – 3.1
First intercourse <18> 1.6
DES, diethylstilbestrol; IUD, intrauterine device.
aSingle values, common odds ratio from homogenous studies; point estimates, range of values from heterogenous studies.

In most tubal implantations, the proliferating trophoblast invades the tubal wall. Ectopic pregnancies in the ampullary portion of the tube are often within the tubal lumen and have not caused tubal rupture, while those in the isthmic portion are more likely to be found outside the lumen, having caused tubal rupture. The degree of trophoblastic invasion of maternal tissues, the age and viability of the pregnancy, and the site of implantation determine the sequence of clinical events. As the trophoblasts proliferate, the growth may extend from the luminal mucosa, into the muscularis and lamina propria, through to the serosa and, ultimately, full thickness even into large blood vessels in the broad ligament. With vascular disruption, bleeding takes place that distorts the tube, stretches the serosa, and causes pain. The embryo is abnormal and degenerates in about 80% of cases. If left untreated, spontaneous tubal abortion occurs in about 50% of tubal ectopic pregnancies and may often be clinically silent. Likewise, spontaneous tubal abortion with hemorrhage can occur with bleeding that is self-limited. However, the remaining cases of ectopic pregnancy will eventually cause tubal rupture and are associated with significant and possibly life-threatening hemorrhage. As noted previously, this complication is most likely to occur in the isthmic part of the tube, which has limited distensibility. Chronic tubal rupture with extension into the broad ligament can produce a pelvic hematoma that can last for several weeks. Unruptured ectopic pregnancies can produce a chronic course, with persistently elevated β-human chorionic gonadotropin (β-hCG) levels that may last for weeks.

Fig.1 Implantation sites for ectopic pregnancy following natural cycles and ART.

Besides tubal disease, factors inherent to the embryo itself may theoretically lead to premature implantation in the tube, prior to its entry into the uterine cavity. However, studies have not supported the theory that genetic or other morphologic abnormalities of the embryo cause implantation at an ectopic site, as the rate of chromosomal abnormalities in surgically excised tubal pregnancies is comparable to that expected for gestational and age-related factors.Other molecular-level factors that may be responsible for the molecular dialog between embryo and implantation site, or cell-cell and cell-extracellular matrix interactions, are being studied for their possible role in aberrant implantations.

Risk Factors

Ectopic pregnancy most often is associated with risk factors leading to tubal epithelial damage, which alters gamete and embryo transport. Meta-analyses identify the risk factors listed in Table 1 as the most influential.

Tubal Damage and Infection

Documented tubal pathology carries a 3.5-fold common adjusted odds ratio for ectopic pregnancy. Patients with a previous ectopic pregnancy are six to eight times more likely to experience another ectopic pregnancy, and 8% to 14% of patients experience more than one ectopic pregnancy. The approximate recurrent ectopic pregnancy rate is 13% after a history of one ectopic and 28% after two previous ectopics. Patients with a history of tubal surgery have a 21-fold common adjusted odds ratio of ectopic pregnancy, but it is not clear if it is the tubal disease itself or the surgery required for the disease.

Tubal pathology frequently results from pelvic infections. Patients with a history of pelvic infections, including gonorrhea, serologically confirmed chlamydia, and nonspecific pelvic inflammatory disease, have a twofold to fourfold higher risk of developing an ectopic pregnancy. The ectopic pregnancy rate is 4% in women with laparoscopically documented salpingitis, compared with 0.7% in women with normal-appearing tubes. In evaluating histologic specimens of ectopic pregnancy, microscopic evidence of salpingitis is present in 38% of cases. Recurrent episodes of pelvic infections increase the likelihood of tubal occlusions: 12.8% after one infection, 35.5% after two infections, and 75% in women with three or more infections.

Salpingitis Isthmica Nodosa

Salpingitis isthmica nodosa is a disease defined by an anatomic thickening of the proximal portion of the fallopian tubes at the junction with the uterus and is histologically characterized by multiple luminal diverticula. The etiology of this disease is not known; however, this pattern of tubal pathology increases the incidence of ectopic pregnancy by 52% in age- and race-matched controls.

Diethylstilbestrol

Prenatal exposure to diethylstilbestrol (DES) alters fallopian tubal development, resulting in absent or minimal fimbrial tissue, a small tubal os, and decreased length and caliber of the tube. This abnormal tubal anatomy is associated with a fivefold increase in the risk for ectopic pregnancy.

Cigarette Smoking

Patients who smoke cigarettes are at a slightly increased risk for ectopic pregnancy. It is difficult to conceptualize the link between ectopic pregnancy and cigarettes. Theories include impaired immunity in smokers predisposing them to pelvic infections, alterations in tubal motility, or a representation of a lifestyle associated with an increased risk of tubal infection.

Contraception

Intrauterine devices (IUDs) have been associated with ectopic pregnancy. A multicenter case-controlled study conducted by the World Health Organization in ten countries found an odds ratio of 6.4 for ectopic pregnancy in current IUD users compared with pregnant controls, whereas the odds ratio was only 0.5 when the comparison was made with nonpregnant controls. Similarly, in the Oxford Study of 17,032 contraceptive users, the proportion of unplanned pregnancies that were ectopic was higher in women using IUDs compared with women taking oral contraceptives. Thus, IUDs effectively prevent pregnancy, but if pregnancy does occur in a woman using an IUD, there is increased likelihood that the pregnancy will be ectopic.

Tubal ligation carries a similar risk for ectopic pregnancy to what is observed with current IUD use. A meta-analysis using case-controlled studies found the odds ratio for tubal sterilization to be 9.3 when compared with pregnant controls and 0.52 when compared with nonpregnant controls, a finding confirmed by two additional multicenter case-controlled trials. As with the IUD, tubal ligations effectively prevent pregnancy, but if pregnancy does occur, the suspicion for an ectopic pregnancy should be high.

Tubal sterilization by using electrocoagulation procedures are associated with higher ectopic pregnancy risk than other methods of tubal sterilization, possibly resulting from tubal recanalization or uteroperitoneal fistula formation. Uteroperitoneal fistulas have been found in up to 75% of hysterectomy specimens from women with previous tubal ligations in which the tubes were cauterized flush with the uterus.

Oral contraceptives are associated with a reduced risk of ectopic pregnancy when compared with nonpregnant controls but with elevated risk when compared with pregnant controls. This protection is presumably due to the suppression of ovulation by oral contraceptives. It is therefore not surprising that patients who take emergency contraception, such as oral contraceptives after fertilization, are at substantial risk for an ectopic pregnancy. This has been attributed to altered tubal motility, but this etiology remains controversial.

Barrier contraception (condoms, spermicides, and diaphragms) also reduces the odds ratio of ectopic pregnancy. An additional advantage may be attributed to the decreased risk of sexually transmitted diseases in women using barrier methods.

Evidence-Based Recommendation

Women with a previous ectopic pregnancy, tubal surgery, tubal pathology, or with prenatal DES exposure are at high risk for ectopic pregnancy. Women who have experienced genital infections, infertility, or more than one sexual partner have a moderate risk of ectopic pregnancy. Previous pelvic or abdominal surgery, smoking, vaginal douching, or an early age of first sexual intercourse have only a slightly increased risk of ectopic pregnancy.

Contraception, if used properly, is an effective way of reducing pregnancy, both intrauterine and ectopic. If pregnancy occurs in women with an IUD, after tubal ligation, or following emergency contraception, suspicion for ectopic pregnancy should be high. (Strength of recommendation: A.)

Signs and Symptoms

The classic symptoms of an ectopic pregnancy are abdominal or pelvic pain and vaginal bleeding or spotting in the context of a positive pregnancy test. However, these symptoms may be variable, range from mild to severe, and are neither sensitive nor specific for the diagnosis of ectopic pregnancy. Today, many ectopic pregnancies never produce symptoms; rather, they are diagnosed and treated in a timely fashion because the patient is identified as high risk. Table 5.1 summarizes and weighs risk factors that should be examined in every woman who has just been identified as being pregnant. However, the medical and economic benefits of screening asymptomatic women, including those who are considered at high risk, are outweighed by the still overall low incidence of ectopic pregnancy and the high false-positive rate of doing so. Thus, universal screening of all women, including some considered at higher risk, is not recommended. Since at least 40% to 50% of patients with proven ectopic pregnancies have no risk factors, absence of these factors is not wholly reassuring and does not exclude an ectopic pregnancy. Unfortunately, early diagnosis is not always achievable, and fallopian tube rupture secondary to ectopic pregnancy remains a relatively frequent clinical occurrence.

The most common signs are detected on abdominal examination. Abdominal tenderness is present in 90% of patients and rebound tenderness in 70%. The pelvic examination is usually nonspecific; cervical motion tenderness is present in up to two thirds of patients, while a tender adnexal mass is present in 10% to 50%. Pain radiating to the shoulder, syncope, and shock, as a result of hemoperitoneum, occur in up to 20% of patients and are indications for immediate surgical intervention.

Diagnosis

Ectopic pregnancy can be diagnosed as early as 4.5 weeks gestation. Unfortunately, visualizing an ectopic pregnancy this early frequently is not possible. More importantly, traditional laparoscopic visualization (Figs. 5.2, 5.3, 5.5) is now rarely necessary. Routine diagnostic tests are serial measurements of β-hCG, ultrasonography, uterine sampling via manual vacuum extraction or curettage, and, in some instances, serum progesterone levels.

Outpatient diagnosis of ectopic pregnancy by using various algorithms has been shown to be safe and effective without need for hospitalization even when the diagnosis is equivocal. The clinical algorithm in Figure 5.4 is highly efficacious in diagnosing ectopic pregnancy.

The diagnosis of ectopic pregnancy begins by excluding a normal intrauterine pregnancy. Transvaginal ultrasound examination should identify an intrauterine pregnancy with nearly 100% accuracy for gestations greater that 5 weeks by identifying structures such as a gestational sac, a yolk sac, and fetal pole with later cardiac motion (usually seen around 6 weeks). Because of the inaccuracies inherent in pregnancy dating, β-hCG is often used as a surrogate marker for pregnancy dating. As will be further discussed below, an intrauterine pregnancy should be visualized at the “discriminatory cutoff” of β-hCG, a level corresponding to 1,500 to 2,500 IU/L (depending on operator and equipment used) with near 100% sensitivity. These β-hCG thresholds are not universal, and each institution must identify its own values to avoid terminating normal intrauterine pregnancies. The absence of such implies an abnormal gestation. If the pregnancy is earlier than the aforementioned 5 weeks and/or the β-hCG is below the “discriminatory cutoff”, then serial β-hCG measurements aid in the diagnosis and determine the need for intervention.

Figure 2 Laparoscopic visualization of an isthmic ectopic pregnancy.

Figure 3 Laparoscopic visualization of an ampullary ectopic pregnancy.

Serial β-Human Chorionic Gonadotropin Determinations

The advent of radioimmunoassay (RIA) and specific antiserum to the β-subunit of hCG has allowed for the accurate quantification of β-hCG and the ability to closely follow trends in the rise and fall of this hormone, detecting low β-hCG concentrations in urine and serum, 20 mIU/mL down to 1 mIU/mL, respectively. Currently, β-hCG is almost exclusively assayed using the third International Reference Preparation (IRP), a standard very similar to the original first IRP.

The β-hCG, produced by trophoblastic cells in normal pregnancy, has long been accepted to rise at least 66% and up to twofold every 2 days. Recent data has shown that the minimum rise for a potentially viable pregnancy that presents with pain and/or vaginal bleeding may be as low as 53% in 2 days, based on the 99th percentile confidence interval (CI) around the mean of the curve of normal β-hCG rise. Thus, intervention for a β-hCG rise of less than 66% over 2 days, a practice supported by previous data, may potentially interrupt a normally developing intrauterine pregnancy. This generally applies to β-hCG values below 10,000 mIU/mL.

Figure 4 Diagnostic algorithm for ectopic pregnancy. (From Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol 2006;107:402)

Figure 5 Ultrasonogram of free fluid noted under the liver edge above the right kidney. Confirmed to be blood from a ruptured ectopic pregnancy at the time of surgery. (Courtesy of R. Mangal, M.D., Obstetrics/Gynecologic Associates, Houston, TX.)

Eight-five percent of abnormal pregnancies, whether intrauterine or ectopic, have impaired β-hCG production with an abnormal rate of β-hCG rise. β-hCG levels that plateau or fail to rise normally along with a low serum progesterone value should be considered nonviable. Rapidly declining β-hCG values (at least 21% to 35% in 2 days) are likely consistent with a miscarriage that may resolve spontaneously but could still represent a spontaneously resolving ectopic gestation. In such situations, β-hCG levels should be followed serially until no longer detectable, indicating complete resolution of the pregnancy, regardless of the implantation site.

If a viable intrauterine gestation is not visible by transvaginal ultrasonography when the β-hCG is above the “discriminatory cutoff” and no fetal heartbeat can be visualized in the adnexa, uterine curettage or manual vacuum extraction can be performed. This intervention is necessary to accurately differentiate between an abnormal intrauterine gestation (spontaneous abortion) and an ectopic pregnancy. Either treatment of a nonviable intrauterine pregnancy is performed or ectopic pregnancy is diagnosed when the uterine contents fail to demonstrate presence of chorionic villi on histologic examination or the β-hCG levels do not fall appropriately postuterine evacuation.

If histologic examination is not readily available, β-hCG determinations are further employed for diagnosis after uterine curettage. If the β-hCG fails to decline by 15% after 12 to 24 hours from a level drawn immediately before surgery, the pregnancy is presumed ectopic and treatment should be initiated. To definitively confirm resolution of the pregnancy in the absence of a tissue diagnosis, β-hCG levels should be followed weekly until undetectable.

Progesterone

The diagnostic algorithm presented here does not include the measurement of serum progesterone levels, a test whose results are not immediately available to aid in diagnosis in many clinical settings. Although progesterone levels are higher in intrauterine pregnancies than in ectopic pregnancies, there is no established cutoff to use to discriminate between these two entities. A meta-analysis has shown that although low progesterone levels can identify patients at risk for ectopic pregnancy, this test alone is insufficient to diagnose ectopic pregnancy with certainty. In addition, a low progesterone level of less than 5 ng/mL can rule out a normal pregnancy with almost 100% accuracy but does not differentiate whether that pregnancy is an abnormal one in the uterus or at an ectopic site.

Ultrasonography

Although the uterus and adnexa may be evaluated by an abdominal or pelvic examination, transvaginal ultrasonography reliably detects intrauterine gestations when the β-hCG levels are between 1,500 and 2,500 mIU/mL (third IRP), or as early as 1 week after missed menses. An intrauterine gestation should almost always be visualized when the β-hCG level is greater than 2,000 mIU/mL.

Diagnosis of an ectopic pregnancy can be made with 100% sensitivity but with low specificity (15% to 20%) if an extrauterine gestational sac containing a yolk sac or embryo is identified. A complex adnexal mass without an intrauterine pregnancy improves specificity to 21% to 84% at the expense of lower sensitivity (93.0% to 99.5%). In reviewing the literature, the presence of any noncystic, extraovarian adnexal mass in the absence of an intrauterine gestation was diagnostic of an ectopic pregnancy with 98.9% sensitivity, 96.3% positive predictive value, 84.4% specificity, and a 94.8% negative predictive value (Fig. 6). Despite the high resolution of transvaginal ultrasonography, an adnexal mass will not be found in 15% to 35% of patients with an ectopic pregnancy, particularly in early stages. Some sonographic images, such as the pseudogestational sac, may mislead even an experienced examiner to falsely diagnose a gestational sac. This is a collection of fluid within the endometrial cavity, usually in a central as opposed to eccentric location that occurs due to bleeding from the decidualized endometrium when an extrauterine gestation is present.

Figure 5.6 Transvaginal ultrasonographic illustration of tubal ectopic gestation.

Serial β-hCG concentrations and transvaginal ultrasonography predict ectopic pregnancy with a positive predictive value of 95%. Ultrasonography should be used to document the presence or absence of an intrauterine pregnancy when the β-hCG levels have risen above the designated discriminatory cutoff zone.

However, in those patients with an “indeterminate” ultrasound, 25% have an ectopic pregnancy. Therefore, serial β-hCG and ultrasonography alone cannot diagnose all ectopic pregnancies. In order to make the definitive diagnosis and differentiate an abnormal intrauterine from an ectopic pregnancy, uterine evacuation for tissue diagnosis is necessary. In order to minimize the inadvertent interruption of a desired intrauterine pregnancy, a high (not low) discriminatory zone should be used before uterine evacuation is considered.

Uterine Evacuation

Uterine curettage or manual vacuum extraction is necessary when a transvaginal ultrasonogram and a rising or plateauing β-hCG level below the cutoff value are not sufficient for diagnosis. With this procedure, tissue can be obtained to look for intrauterine products of conception. If present, the patient had an abnormal intrauterine pregnancy and now a completed abortion; if negative, the patient has an ectopic pregnancy needing further management. If histologic examination is not available, then a guideline of a decrease in the β-hCG level of 15% or more 12 hours after curettage is diagnostic of a complete abortion. If the β-hCG titer plateaus or rises and the trophoblast was not removed by curettage, an ectopic pregnancy is likely.

Evidence-Based Recommendation

Serial β-hCG determinations, transvaginal ultrasonography, and uterine sampling allow for definitive diagnosis of ectopic pregnancy. A confirmatory laparoscopy is rarely necessary. (Strength of recommendation: A.)

Acute Bronchitis

Posted in Interna on 22 November 2009 by kadaverboy

Acute bronchitis is one of the most common diagnoses made by primary care physicians in the United States and accounts for nearly 10 million office visits per year. Acute bronchitis is a transient, self-limited inflammatory process of the upper respiratory tract, specifically the trachea and bronchi. Antibiotics are overprescribed to patients with acute bronchitis; this practice has raised significant concern related to the worldwide rise of antibiotic resistance, which is viewed as one of the world’s most pressing public health problems.

Acute bronchitis manifests as an acute respiratory illness of less than 3 weeks’ duration, with or without sputum production. Acute bronchitis is a clinical diagnosis and must be distinguished from other respiratory diseases, such as pneumonia, acute exacerbation of chronic bronchitis (episode of worsening of symptoms and expiratory airflow obstruction in patients with chronic obstructive pulmonary disease), and the onset of asthma. Most cases of acute bronchitis occur in the fall and winter. The etiology of acute bronchitis is infectious, and viruses appear to be the cause of most cases. Influenzas A and B are the most common viruses isolated, although a wide variety of infectious agents have been identified, such as adenovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, coxsackievirus, Mycoplasma pneumoniae, Bordetella pertussis, and Chlamydia pneumoniae.

Diagnosis of acute bronchitis is based on findings of a prominent cough that may be accompanied by wheezing and sputum production. Most patients are otherwise healthy and without preexisting respiratory disease. Nonspecific constitutional symptoms may also be part of acute bronchitis. Appropriate management of acute bronchitis is essential because it is one of the most common illnesses that present to physicians in the outpatient setting. Antibiotics are often prescribed unnecessarily for acute bronchitis and other respiratory tract illnesses; these prescriptions may potentially lead to adverse events (i.e., allergic reactions and gastrointestinal side effects) and bacterial resistance. Other medications, such as inhaled bronchodilators and antitussives, are often prescribed for acute bronchitis despite questionable evidence to support their routine use.

Pathophysiology of acute bronchitis involves an acute inflammatory response involving the mucosa of the trachea and bronchi, resulting in injury to the respiratory tract epithelium. Sputum production is increased and bronchoconstriction (potentially resulting in airflow obstruction and wheezing) can occur. Positron emission tomography (PET) of a patient with acute bronchitis confirms that the primary inflammatory changes occur in the trachea and bronchi and not the remainder of the lower respiratory track.

 

CURRENT DIAGNOSIS

1. Normal healthy adult with cough

 

2. Predominance of cough

3. Lasts 1 to 3 weeks

4. With or without sputum

5. Can be accompanied by other respiratory and constitutional symptoms

6. Absence of abnormal vital signs and physical exam suggesting pneumonia,particularly

Heart rate >100 beats per minute

Respiratory rate >24 breaths per minute

Temperature >100.4°F (38°C)

Lung findings suggest a consolidation process

Diagnosis

Cough, phlegm (which may be purulent as both bacteria and viruses can cause purulent sputum), and wheezing help differentiate acute bronchitis from upper respiratory infections such as pharyngitis and sinusitis. Acute bronchitis must be differentiated from acute bacterial pneumonia. The absence of abnormalities in vital signs (heart rate >100 bpm, respiratory rate >24 breath/min, oral temperature >100.4°F [38°C] and physical examination of the chest) supports the diagnosis of acute bronchitis and makes the need for chest radiography unnecessary in most cases. The treatment and outcome of acute bronchitis and pneumonia are very different; a chest radiograph should always be obtained if there is uncertainty about the diagnosis. Chest radiography will demonstrate no lung infiltrates in a patient with acute bronchitis. In contrast, lung infiltrates are present in pneumonia. Pertussis or whooping cough should be considered in adults with cough in the setting of what appears to be an upper respiratory infection, even in those previously immunized. Typically, the cough of pertussis, unlike acute bronchitis, lasts for longer than 3 weeks. Other respiratory diseases, such as previously undiagnosed asthma, can also mimic acute bronchitis, although several features differentiate asthma from acute bronchitis (see Section 12). Rapid testing to diagnose influenza viruses A and B (the most common causes of acute bronchitis) as a cause of acute bronchitis should be considered given the availability of effective treatment if initiated in the first 48 hours.

Treatment

ANTIBIOTICS, INHALED BRONCHODILATORS, AND ANTITUSSIVES

Existing evidence does not support the routine use of antibiotics for uncomplicated cases of acute bronchitis. Although most cases of acute bronchitis are caused by viral infections, upwards of 60% of patients are prescribed antibiotic therapy, which is contributing to the rise of bacterial resistance to commonly used antibiotics. Meta-analyses examining the effectiveness of antibiotic therapy in patients without underlying lung disease suggest no consistent effect of antibiotics on the severity or duration of acute bronchitis. A recent study evaluated children and patients with colored sputum and found that they also did not benefit from antibiotics. This study also found that compared to other populations, the elderly were less likely to benefit from antibiotics. Smokers with acute bronchitis are even more likely to be prescribed antibiotics.

Their response to antibiotics was either equal to or worse than that of nonsmokers.

 

CURRENT THERAPY

Antibiotics not routinely recommended

 

If influenza is highly probable and patient is presenting within the first 48 hours, consider treatment with :

a. Oseltamivir (Tamiflu) 75 mg PO bid with food for 5 days (influenza A/B)

b. Zanamivir (Relenza) 10 mg bid by inhalation for 5 days (influenza A/B) [*]

c. Amantadine (Symmetrel) 100 mg bid or 200 mg once daily for 5 days (influenza A) [*]

d. Rimantadine (Flumadine) 100 mg bid for 5 days (influenza A)

In patients with evidence of bronchial hyperresponsiveness, consider treatment with

a. β2-agonists for 1 to 2 weeks

b. Antitussives in those with cough for 2 to 3 weeks

c. Antipyretics and analgesics as needed

d. Smoking cessation

Education: cough likely to last 3 weeks or more.

Due to emergence of antiviral resistance, use of these agents has been discouraged by the CDC.

One possible reason for overuse of antibiotics is the concern by physicians about patient satisfaction. Studies show that patients presenting to the doctor expecting antibiotics were more likely to be prescribed antibiotics; studies also suggest that satisfaction is more related to appropriate patient education than to receiving antibiotics. Patient education should include information regarding the duration of symptoms associated with acute bronchitis. It was found that patients presented on average after 9 days of cough and that the cough persisted for an additional 12 days after the physician visit. This information can impart a realistic expectation of illness duration to the patient.

If influenza is highly suspected and the patient presents within 48 hours of the onset of symptoms, rapid diagnostic testing and treatment should be considered. Both amantadine (Symmetrel) and rimantadine (Flumadine) are effective for influenza A, and neuraminidase inhibitors, inhaled zanamivir (Relenza), and oral oseltamivir (Tamiflu) are effective for influenzas A and B. If these medications are initiated within the first 48 hours of symptoms (and ideally within 30 hours), the duration of illness can be shortened.

The evidence supporting the use of inhaled bronchodilators for the treatment of the symptoms has been variable. Two small trials reported a shorter duration of cough with the use of inhaled ß-agonists; another study reported benefit in those with evidence of bronchial hyperresponsiveness. Current recommendations support the use of ß-agonists only in patients with evidence of bronchial hyperresponsiveness (wheezing or spirometry demonstrating a forced expiration volume in 1 second [FEV1] <80%>

Antitussive agents have not been shown to improve the acute or early cough but did show some improvements in cough lasting longer than 3 weeks. The current recommendations are to use antitussives, namely dextromethorphan (Benylin) or codeine, in patients with cough of 2 to 3 weeks’ duration.

Acute uncomplicated bronchitis is most often a viral illness in which antibiotics are not routinely indicated. Patients presenting with an acute respiratory illness, who are younger than 65 years old without existing pulmonary disease or other significant comorbid illness, should have a thorough physical examination, including vital signs. If the vital signs are normal and physical examination of the chest is clear, pneumonia can most likely be ruled out. In patients who present within 48 hours of onset of symptoms, influenza should be considered as effective therapy is available for acute bronchitis caused by influenzas A or B. Otherwise, the evidence for treatment with antibiotics does not support their routine use. Bronchodilators should be considered in those with evidence of bronchial hyperresponsiveness; cough suppressants should be considered in those with 2 to 3 weeks of cough. Patient education is an integral part of the treatment, and patients should receive information that provides realistic expectations regarding the duration of cough.

kolestasis Pada Anak

Posted in Pediatric, Uncategorized on 22 November 2009 by kadaverboy

Pendahuluan

Kolestasis adalah suatu sindroma klinis yang disebabkan oleh terganggunya aliran empedu ke usus.

Kolestasis tidak selalu disertai dengan adanya ikterus, terutama pada fase-fase awal penyakit. Karenanya pada beberapa penyakit hepar, ikterus sudah merupakan gejala lanjut karena sebenarnya kolestasisnya sudah berjalan agak lama.

Kolestasis sering menjadi penyebab dari beberapa kelainan hepatobilier dimana kolestasis sendiri mempunyai berbagai etiologi.

Tindakan yang perlu dilakukan terhadap kolestasis tergantung antara lain oleh lokasi kelainannya, intra atau ekstra hepatal yang dapat dibedakan melalui manifestasi klniniknya. Tindakan ini harus segera dilakukan sebelum penderita mencapai usia 2 bulan sebelum terjadinya kerusakan hepar permanen (sirosis).

Adanya kelainan nutrisional yang menyertai kolestasis seperti absorbsi lemak dan vitamin larut lemak harus diperhatikan.

Ada 3 kejadian penting yang terjadi, yang mengakibatkan timbulnya gejala klinis, yaitu:

  1. Terganggunya aliran empedu masuk ke dalam usus
  2. Akumulasi empedu dalam darah
  3. Kerusakan sel hepar sebagai akibat menumpuknya komponen empedu

Pada bayi, kolestasis sering diartikan sebagai “conjugated hyperbilirubinemia” disertai dengan perubahan biokimia dan patologi yang menunjukkan adanya kerusakan sel hepar.

Etiologi dan Patogensa

Sebenarnya gangguan transpor empedu bisa terjadi sejak awal pembentukkannya. Saat ini dibedakan 2 fase gangguan transpor yang dapat terjadi pada kolestasis.

Fase 1: gangguan pembentukan bilirubin oleh sel hepar, yang dapat terjadi karena bebrbagai sebab, antara lain:

  • Adanya kelainan bentuk (distorsi, sirosis)
  • Berkurangnya jumlah sel hepar (“deparenchymatised liver”)
  • Gangguan fungsi sel hepar

Pada keadaan ini, berbagai bahan yang seharusnya dibuang melalui empedu akan tertumpuk dan tidak mencapai usus yang akan sangat mengganggu pencernaan sehingga terjadi berbagai defisiensi, kondisi toksik, serta penumpukan pigmen empedu yang menyebabkan ikterus. Gangguan fase pertama ini disebut kolestasis primer.

Fase 2: gangguan transpor yang terjadi pada perjalanan dari bilirubin mulai dari hepar ke kandung empedu sampai ke usus.

Bayi pada minggu pertama sering menunjukkan gejala kolestasis dengan tinja akolis/hipokolis, karena proses kolestasis yang terjadi fisiologis akibat masih kurang matangnya fungsi hepar. Namun harus diwaspadai bila hal ini terjadi pada minggu-minggu berikutnya. Hepar hampir selalu membesar sejak dari permulaan penyakit. Pembesaran limpa pada 2 bulan pertama lebih sering terdapat pada kolestasis intarhepatik dari pada ekstrahepatik, sedangkan pada bulan-bulan berikutnya lebih banyak pada kolestasis ekstrahepatik.

GAMBARAN KLINIS

Gambaran klinis pada kolestasis pada umunya disebabkan karena keadaan-keadaan:

  1. Terganggunya aliran empedu masuk ke dalam usus
    • Tinja akolis/hipokolis
    • Urobilinogen/sterkobilinogen dalam tinja menurun/negatif
    • Urobilin dalam air seni negatif
    • Malabsorbsi lemak dan vitamin yang larut dalam lemak
    • Steatore
    • Hipoprotrombinemia
  2. Akumulasi empedu dalam darah
  • Ikterus
  • Gatal-gatal
  • Hiperkolesterolemia
  • Anatomis
  1. Kerusakan sel hepar karena menumpuknya komponen empedu

-         Akumulasi pigmen

-         Reaksi keradangan dan nekrosis

  • Fungsional

-         Gangguan ekskresi (alkali fosfatase dan gama glutamil transpeptidase meningkat)

-         Transaminase serum meningkat (ringan)

-         Gangguan ekskresi sulfobromoftalein

-         Asam empedu dalam serum meningkat

Tanda-tanda non-hepatal sering pula membantu dalam diagnosa, seperti sindroma polisplenia (situs inversus, levocardia, vena cava inferior tidaka ada), sering bersamaan dengan atresia bilier: bentuk muka yang khas, posterior embriotokson, serta adanya bising pulmunal stenosis perifer, sering bersamaan dengan “paucity of the intrahepatic bile ductules” (arterio hepatic displasia/Alagille’s syndrome) nafsu makan yang jelek dengan muntah, “irritable”, sepsis, sering karena adanya kelainan metabolisme seperti galaktosemia, intoleransi froktosa herediter, tirosinemia.

Neonatal hepatitis lebih banyak pada anak laki, sedangkan atresia bilier ekstrahepatal lebih banyak pada anak perempuan.

PENDEKATAN DIAGNOSA

Pada bayi dengan kolestasis harus dibedakan antara kolestasis intra- atau ekstrahepatal dengan tujuan utama memperbaiki/ mengobati keadaan-keadaan yang memang dapat diperbaiki/diobati.

Sebagai tahap pertama dalam pendekatan diagnosa, harus dibuktikan apakah ada kelainan hepatobilier atau tidak. Pemeriksaan yang perlu dilakukan pada tahap ini adalah:

-         Hapusan darah tepi

-         Bilirubin dalam air seni

-         Sterkobilinogen dalam air seni

-         Tes fungsi hepar yang standar: Heymans vd Bergh, SGOT, SGPT, alkali fosfatase serta serum protein

Bila dari pemeriksaan tersebut masih meragukan, dilakukan pemeriksaan lanjutan yang lebih sensitif seprti BSP/kadar asam empedu dalam serum. Bila fasilitas terbatas dapat hanya dengan melihat pemerikasaan bilirubin air seni. Hasil positf menunjukkan adanya kelainan hepatobilier.

Bila ada bukti keterlibatan hepar maka dilakukan tahap berikutnya untuk membuktikan:

  1. Kelainan intra/ekstrahepatal
  2. Mencari kemungkinan etiologi
  3. Mengidentifikasi kelainan yang dapat diperbaiki/diobati

Pemeriksaan yang dilakukan adalah:

  1. Terhadap infeksi/bahan toksik
  2. Terhadap kemungkinan kelainan metabolik
  3. Mencari data tentang keadaan saluran empedu

Untuk pemeriksaan terhadap infeksi yang penting adalah:

Virus

  • Virus hepatotropik: HAV, HBV, non A non B, virus delta
  • TORCH
  • Virus lain: EBV, Coxsackie’s B, varisela-zoster

Bakteri: terutama bila klinis mencurigakan infeksi kuman leptospira, abses piogenik

Parasit: toksoplasma, amuba, leismania, penyakit hidatid

Bahan toksik, terutama obat/makanan hepatotoksik

Pemeriksaan kelainan metabolik yang penting:

  • Galaktosemia, fruktosemia
  • Tirosinosis: asam amino dalam air seni
  • Fibrosis kistik
  • Penyakit Wilson
  • Defisiensi alfa-1 antitripsin

Data tentang saluran empedu diperoleh melalui pemeriksaan:

  1. Rose Bengal Excretion (RBE)
  2. Hida Scan
  3. USG
  4. Biopsi hepar

Ket: no. 1 dan 2 belum dapat dilakukan di Indonesia

Bila dicurigai ada suatu kelainan saluran empedu dilakukan pemeriksaan kolangiografi.

PENATALAKSANAAN

Penggobatan paling rasional untuk kolestasis adalah perbaikan aliran empedu ke dalam usus. Pada prinsipnya ada beberapa hal pokok yang menjadi pedoman dalam penatalaksanaannya, yaitu:

  1. Sedapat mungkin mengadakan perbaikan terhadap adanya gangguan aliran empedu
  2. Mengobati komplikasi yang telah terjadi akibat adanya kolestasis
  3. Memantau sedapat mungkin untuk mencegah kemungkinan terjadinya keadaan fatal yang dapat mengganggu proses regenerasi hepar
  4. Melakukan usaha-usaha yang dapat mencegah terjadinya gangguan pertumbuhan
  5. Sedapat mungkin menghindari segala bahan/keadaan yang dapat mengganggu/merusak hepar

Dalam hal ini pengobatan dibagi dalam 2 golongan besar, yaitu:

  1. Tindakan medis
    • Perbaikan aliran empedu: pemberian fenobarbital dan kolestiramin, ursodioxy cholic acid (UDCA).
    • Aspek gizi: lemak sebaiknya diberikan dalam bentuk MCT (medium chain triglyceride) karena malabsorbsi lemak. Diberikan tambahan vitamin larut lemak
  2. Tindakan bedah

Tujuannya untuk mengadakan perbaikan langsung terhadap kelainan saluran empedu yang ada.

Kontribusi Prebiotik pada formula untuk pemeliharaan ekosistem normal usus

Posted in Pediatric on 22 November 2009 by kadaverboy

Kontribusi Prebiotik pada formula untuk

pemeliharaan ekosistem mikrobiota normal pada usus


PENDAHULUAN

Mikroflora normal pada usus manusia adalah suatu mikroekosistem yang sangat komplek, yang untuk mempertahankan homeostasis kolonisasinya diperlukan adanya nutrien yang masuk kedalam usus, mikrobiota usus adalah sangat penting untuk host (pejamu) dalam arti fungsi metabolik dan ketahanan terhadap infeksi bakteri terutama gastroenteritis, (Dai D, 1999), kadar lemak darah, sifat anti tumor, toleransi laktosa, imunitas usus (Collins, 1999). Diet dan lingkungan akan mempengaruhi proses kolonisasi. Pada manusia (bayi) kolonisasi bakteri segera setelah lahir, pada bayi yang mendapat asi kolonisasi bakteri dominan oleh bifidobacteria dari pada oleh bakteri yang membahayakan, sedangkan pada bayi yang minum susu formula kolonisasi didominasi oleh bakteri coliform, enterococci dan bacteroides (Collins, 1999;  Dai D, 1999). Kolonisasi adalah proses yang bertahap (gradual) yang ditentukan oleh banyak faktor antara lain, komposisi mikroflora usus ibu, lingkungan dan mungkin juga aspek genetik, derajat kebersihan, cara persalinan, pemakaian antibiotika dan perawatan inkubator terutama bayi prematur, proses kolonisasi bakteri bifidobacterium akan terlambat dan akan terjadi kolonisasi oleh kuman yang patogen yang mudah overgrowth (tumbuh lampau) dan kemungkinan besar akan terjadi translokasi (Kirjavainen, 1999). Pada bayi yang minum asi, mikrobiota usus didominasi oleh bifidobacterium dan lactobacillus bifidus (probiotik) oleh karena asi mengandung probiotik dan prebiotik (oligosaccharida) yang merupakan faktor pertumbuhan untuk probiotik, bayi yang telah disapih lama kelamaan kolonisasi probiotik berkurang dan bayi yang minum susu formula saja masukan probiotik dapat dikatakan tidak ada sehingga mikroekosistem menjadi tidak normal. Sebenarnya kolonisasi oleh probiotik untuk membentuk mikroekosistem yang normal dapat dimanipulasi melalui pengaturan diet yang mengandung prebiotik, probiotik atau kombinasi keduanya (sinbiotik atau eubiotik) yang dalam hal ini merujuk pada komponen yang terdapat pada asi. Membicarakan prebiotik tak dapat dipisahkan dengan probiotik oleh karena target prebiotik adalah memacu pertumbuhan yang selektif dari bakteri probiotik (Roberfroid, 2000).

Batasan

Probiotik : terdapat banyak macam definisi yang yang dibuat, tetapi yang banyak dipakai, berlaku secara saintifik dikemukakan oleh Fullerdan Gibson yaitu bakteri hidup yang diberikan sebagai suplemen makanan yang mempunyai pengaruh menguntungkan  pada kesehatan baik pada manusia dan binatang, dengan memperbaiki keseimbangan mikroflora intestinal (Fuller, 1991; Gibson, 1995; Gibson, 2000). Mikroflora yang digolongkan sebagai probiotik adalah yang memproduksi lactic acid terutama misalnya Lactobacilli dan Bifidobacteria walaupun jenis yang lain juga ada.

Pertemuan ilmiah Gizi Jatim Garden Palace 13/1/2000

Probiotik yang efektif harus memenuhi beberapa kriteria :

1) memberikan efek yang menguntungkan pada host, 2) tidak patogenik dan tidak toksik, 3) mengandung sejumlah besar sel hidup, 4) mampu bertahan dan melakukan kegiatan metabolisme dalam usus, 5) tetap hidup selama dalam penyimpanan dan waktu digunakan, 6) mempunyai sifat sensori yang baik, 7) diisolasi dari host (Fuller, 1991).

Efek kesehatan yang menguntungkan dari probiotik adalah :

1) memperbaiki keluhan malabsorsi laktosa, 2) meningkatkan ketahanan alami terhadap infeksi di usus, 3) supresi kanker, 4) mengurangi kadar kholesterol darah, 5) memperbaiki pencernaan (Fuller, 1991), 6) stimulasi imunitas gastrointestinal (McCracken, 1999; McFarlane, 1999).

Prebiotik, adalah nondigestible food ingredient yang mempunyai pengaruh baik terhadap host dengan memicu aktivitas, pertumbuhan yang selektif, atau keduanya terhadap satu jenis atau lebih bakteri penghuni kolon (Salminen, 1998; Gibson, 2000; Roberfroid, 2000). Prebiotik pada umumnya adalah karbohidrat yang tidak dicerna dan tidak diserap biasanya dalam bentuk oligosaccharide (oligofructose) dan dietary fiber (inulin) (Reddy, 1998; Grizard, 1999; Reddy, 1999).

Food ingredient yang diklasifikasikan sebagai prebiotik harus:

1) tidak dihidrolisa dan tidak diserap dibagian atas traktus gastrointestinal sehingga dapat mencapai kolon tanpa mengalami perubahan struktur dan tidak diekskresikan dalam tinja (Grizard, 1999), 2) substrat yang selektif untuk satu atau sejumlah mikroflora komensal yang menguntungkan dalam kolon, jadi memicu pertumbuhan bakteria yang aktif melakukan metabolisme, 3) mampu merubah mikroflora kolon menjadi komposisi yang menguntungkan kesehatan (Collin, 1999; McFarlane, 1999; Roberfroid, 2000). Supaya lebih efektif kerja prebiotik fermentasi selektif adalah hal yang sangat esensial (Gibson, 1998).

Bifidobacteria adalah target yang baik untuk prebiotik.

Sinbiotik (Eubiotik), kemungkinan yang lain untuk managemen mikroflora adalah menggunakan sinbiotik yaitu kombinasi probiotik dan prebiotik. Penambahan mikroorganisme hidup (probiotik) dan substrat (prebiotik) untuk pertumbuhan bakteri misalnya fructooligosaccharide (FOS) dengan bifidobacterium atau lactitol dengan lactobacillus. Keuntungan dari kombinasi ini adalah meningkatkan daya tahan hidup bakteri probiotik oleh karena substrat yang spesifik telah tersedia untuk fermentasi sehingga tubuh mendapat manfaat yang lebih sempurna dari kombinasi ini (Collin, 1999)

Mikrobiota usus

Bakteri bakteri nonpatogen (probiotik) yang berdomisili di usus terutama usus besar dan mengadakan kolonisasi yang membentuk mikroekosistem yang bermanfaat untuk kesehatan pejamu dalam aspek ketahanan terhadap infeksi, aspek metabolik, dan aspek imunologis. Mikrobiota yang paling banyak ditemukan adalah :

Lactobacilli : L. acidophylus, L. casei, L. delbruckii subsp. Bulgaricus, L.   reuter, L. brevis, L. celobiosus, L. curvatus, L. fermentum, L. plantarum.

Gram-positive cocci : Lactococcus lactis subsp. Cremoris, Streptococcus Salvarius subsp. Thermophylus, Enterococcus faecium, S.diaacetylactis, S. intermedius.

Bifidobacteria : B.bifidum, B. adolescentis, B. animalis, B. infantis, B. longum, B.thermophylum (Collin, 1999; McFarlane, 1999).

Usus besar manusia mengandung mikrobiota, suatu komponen yang komplek dan mempunyain kegiatan metabolisme yang ber macam macam. Fungsi utamanya adalah menampung energi dari karbohidrat yang tak tercerna di usus bagian atas, hal ini dapat dimungkinkan oleh karena kemampuan fermentasi dan absorpsi produknya antara lain short chain fatty acid (SCFA), yang mewakili 40-50% energi dari karbohidrat, SCFA, acetat, propionat, butyrat, bahan ini dimetalisir oleh epitel kolon (butyrat), liver (propionat), dan otot (acetat). Mikrobiota juga mempunyai peranan dalm sintesis vitamin B dan vitamin K, dan metabolisme bile acids, sterol dan xenobiotic. Mikrobiota dalam usus sangat responsif terhadap diet karbohitrat yang fermentable, misalnya non starch polysaccharide, resistent starch dan oligosaccharide. Adanya bahan tersebut bakteri akan tumbuh subur dan dapat mensintesis sebanyak 15 gram biomass yang diekskresikan lewat tinja yang mengandung 1 gram bacterial –N (Cumming, 1997).

Komposisi mikrobiota probiotik dalam traktus gastrointestinal dipengaruhi oleh banyak faktor baik ekternal maupun internal. Yang termasuk faktor eksternal adalah jumlah bakteri yang masuk, kebiasaan makan dan minum, komposisi mikrobiota pada ibu, terapi obat-abatan, faktor diet tampaknya mempunyai pengaruh yang kuat, diet yang banyak mengandung oligosaccharide mempengaruhi komposisi spesies dan strain bakteri. Oligosaccharide yang ditambahkan pada formula bayi dapat menurunkan PH usus besar dan dapat meningkatkan populasi bifidobacteria di usus besar sehingga banyak ditemukan di tinja (Gibson, 1998). Terapi antibiotika mempengaruhi suksesi mikrobiota melalui beberapa cara, antibiotika mempunyai efek spesifik terhadap individual komponen dari pada supresi secara umum terhadap mikrobiota, profil mikrobiota setelah mendapat terapi antibiotika menetap walaupun terapi telah dihentikan (Mackie, 1999).

Sumber prebiotik

Prebiotik yang didefinisikan sebagai nondigestible dan nonabsorbable carbohydrat yang mempunyai fungsi regulasi terhadap mikroekosistem mikrobiota probiotik dalam usus sehingga dapat memberikan efek kesehatan pada manusia dan binatang dapat diperoleh dari, 1) asi dalam bentuk human milk oligosaccharide yang hanya <5% dicerna di usus (Gnoth, 2000), 2) secara alami karbohidrat yang mengandung fructooligosaccharides terdapat dalam berbagai sayur dan buah misalnya onion, asparagus, chicory (mengandung inulin), pisang, dan artichoke (Gibson, 1998)

Sintesis prebiotik

Untuk memperoleh oligosaccharides yang akan dipakai sebagai bahan prebiotik dapat dilakukan melalui, 1) ekstraksi langsung polysaccharide alami dari tumbuhan, 2) hidrolisis polysaccharides alami, 3) sintesis ensimatik dengan menggunakan hydrolases dan atau glycocyl transferases, kedua ensim tersebut mengkatalisa reaksi transglikosilasi sehingga terjadi oligosaccharides sintetik dari mono dan disaccharides.

Saat ini di Eropa, inulin type fructan yang dicirikan mengandung ikatan fructosyl unit pada beta-2,1 sukrosa juga dipakai sebagai bahan prebiotik (Grizard, 1999).

Jenis prebiotik

FOS (Fructooligosaccharides), Inulin, GOS (Galactooligosaccharides), Lactulose, Lactitol (Collin, 1999; McFarlane, 1999). Bahan bahan tersebut paling sering dipakai sebagai prebiotik, disamping itu terdapat pula bahan lain yang memenuhi kriteria prebiotik misalnya, xylose, soya, dan mannose (Gibson, 1998).

Syarat prebiotik

Bahan yang dipakai sebagai prebiotik harus memenuhi syarat sebagai berikut, 1) tidak dihidrolisa dan tidak diserap dibagian atas traktus gastrointestinal, 2) substrat yang selektif untuk satu atau sejumlah mikroflora komensal yang menguntungkan dalam kolon, jadi memicu pertumbuhan bakteria yang aktif melakukan metabolisme, 3) mampu merubah mikroflora kolon menjadi komposisi yang menguntungkan kesehatan (Collin, 1999; McFarlane, 1999; Roberfroid, 2000).

Mekanisme kerja prebiotik, interaksi dengan probiotik

Mikrobiota pada kolon manusia dapat memberikan manfaat kesehatan pada host atau potensial patogen. Saat ini banyak dilakukan penelitian untuk memanipulasi komposisi mikrobiota kolon dalam upaya memperoleh aspek potensial yang menguntungkan untuk host. Pendekatan melalui prebiotik, suatu komponen yang tidak hidup dari makanan (non-viable food components) yang secara spesifik difermentasi di kolon oleh bakteri probiotik misalnya Lactobacilli, Bifidobakteria. Sebenarnya setiap food ingredient yang masuk kedalam usus besar adalah kandidat prebiotik, namun demikian untuk efektivitas, selektivitas fermentasi adalah sangat esensial. Bahan yang mendapat banyak diperhatikan dan sukses dipakai adalah non digestible oligosaccharide yang termasuk dalam klsifikasi tersebut adalah fructosa, xylosa, soya, galactosa, glukosa, dan mannosa. Oligosakharide yang mengandung fruktosa yang terdapat dalam alam misalnya onion, asparagus pisang, chicori, memenuhi kriteria sebagai prebiotik (Gibson, 1998). Data penelitian menunjukan bahwa fructooligosaccharide (FOS) yang secara spesifik difermentasi oleh bifidobacteria. Mengkomsumsi bahan prebiotik secara signifikan dapat  memodulasi komposisi  mikrobiota kolon  yang menyebabkan bifidobakteria lebih dominan didalam kolon dan banyak ditemukan didalam tinja (Gibson, 1995). Pemberian FOS sebanyak 4 gram / hari dapat bertindak sebagai prebiotik. Untuk pembenaran konsep tersebut memerlukan penilaian bahwa prebiotik memperbaiki komposisi dan aktivitas  mikrobiota usus, dengan metodologi molekuler menilai lebih akurat identitas prebiotik dan mengembangkan bacterial probing strategy, dapat diberikan dalam bentuk bahan asli atau dalam makanan yang telah diproses, memberikan manfaat pada kesehatan (Gibson, 1998)

Manfaat penggunaan prebiotik

Mencermati manfaat penggunaan prebiotik tidak terlepas dari peranan prebiotik untuk meregulasi dan memodulasi mikroekosistem populasi bakteri probiotik. Prebiotik dalam usus terutama usus besar yang difermentasi oleh bakteri probiotik yang menghasilkan short chain fatty acid (SCFA) dalam bentuk acetat, propionat, dan butyrat,

dan L-lactate, carbon dioxide, hidrogen (Grizard, 1999). SCFA tersebut oleh tubuh dapat dipakai sebagai sumber energi, efek stimulasi selektif terhadap pertumbuhan bakteri probiotik terutama bifidobacteria dan lactobacillus akan memberikan efek yang menguntungkan terhadap kesehatan antara lain, 1) memperbaiki keluhan malabsorsi laktosa, 2) meningkatkan ketahanan alami terhadap infeksi di usus oleh kuman patogen, Clostridium perfringen, Escherchia coli, Salmonella, Shigella, Listeria (Gizard, 1999), 3) supresi kanker, 4) memperbaiki metabolisme lipid dan mengurangi kadar kholesterol darah, 5) memperbaiki pencernaan (Fuller, 1991), 6) stimulasi imunitas gastrointestinal (McCracken, 1999; McFarlane, 1999).

Pencermatan terhadap penggunaan prebiotik

Bayi yang mengkonsumsi asi, dimana asi mengandung pre- dan probiotik sehingga mikroekosistem mikrobiota dalam usus didominasi oleh bakteri probiotik yang dapat tumbuh subur oleh karena adanya growth factor yang terdapat pada asi yaitu prebiotik. Setelah disapih tidak ada lagi masukan asi sehingga per-lahan lahan jumlah bakteri probiotik juga akan menurun sehingga mikroekosistem mikrobiota tidak lagi didominasi oleh bakteri probiotik tetapi oleh bakteri yang lain. Pemberian bahan prebiotik tentunya tidak lagi memberi manfaat seperti yang diharapkan. Bila diharapkan mikroekosistem mikrobiota dalam usus tetap didominasi oleh bakteri probiotik maka perlu dipertimbangkan pemberian formula yang mengandung pro- dan prebiotik kepada bayi yang telah disapih sehingga manfaat pro- dan prebiotik yang menguntungkan kesehatan tetap dapat dipertahankan sampai masa anak anak.

Kepustakaan

Collins, Gibson GR, 1999 : Prebiotic, probiotik, and synbiotic : approaches for modulating the microbial ecology of the gut. Am J Clin Nutr 69(5):1052S-1057S.

Cumming JH, MacFarlane GT, 1997 : Role of intestinal bacteria in nutrient metabolism. J Panenter Enteral Nutr 21(6):357-65.

Dai D, Walker WA, 1999 : Protective nutrients and bacterial kolonization in the immature human gut. Adv.Pediatr 46:353-82.

Fuller R, 1991; Probiotics in human medicine. Gut, 32, 439-442.

Gibson GR, Roberfroid MB, 1995 : Dietary modulation of the human colonic microbiota: introduction the concept of prebiotics. J Nutr 125(6):1401-12.

Gibson GR, 1998 : Dietary modulation of the human gut microflora using

prebiotics. Br J Nutr 80(4):S209-12.

Gibson GR, Fuller R, 2000 : Aspect of invitro and invivo researches directed toward identifying probiotics and prebiotics for human use. J Nutr 130(2S Suppl):391S-395S.

Gnoth MJ, Kunz C, Kinne-Saffran E, Rudloff S, 2000 : Human milk oligosaccharieds : Are minimally digested in vitro? J Nutr 130(12):3014-3020.

Grizard D, Barthomeuf C, 1999 : Non-digestible oligosaccharides used as prebiotic agents : mode of production and benefecial effects on animal and human health. Reprod Nutr Dev 39 (5-6):563-88.

Kirjavainen PV, Gibson GR, 1999 : Healthy gut microflora and allergy : factors influencing development of the microbiota. Ann Med 31(4):288-92.

McCracken VJ, Gaskin HR, 1999; Probiotics and the immune system. Horizon Scientific press. http://horizonpress.com/hsp/pro.html 16 Nov 1999.

Mcfarlane GT, Cummings JH, 1999; Probiotics and prebiotics : can regulating the activities of intestinal bacteria benefit health? BMJ, 318: 999-1003.

Mackie RI, Sghir A, Gaskin HR, 1999; Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Nutr, 69: 1035s-45s.

Roberfroid MB, 2000 : Prebiotics and probiotics: are they functional foods? Am J Clin Nutr 2000 Jun;71(6 Suppl):1682S-7S.

Salminen S, Bouly C, Boutron-Ruault MC, Cumming JH, Frank A, Gibson GR, Isolauri E, Moreau MC, Roberfroid M, Rowland I, 1998 : Functional food science gastrointestinal physiology and function. Br J Nutr Suppl 1:S147-71.

Reddy BS, 1998 : Prevention of colon cancer by pre- and probiotics “: evidence from laboratory studies. Br J Nutr 80(4):S219-23.

Reddy BS, 1999 : Possible mechanism by which pro- and prebiotics influence colon carcinogenesis and tumor growth. J Nutr 129 (7 Suppl):1478S-82S.

Hipoksia Ischemic Encephalopaty

Posted in Pediatric on 22 November 2009 by kadaverboy

HIPOXIC ISCHAEMIC ENCEPHALOPHATY

(ENSEFALOPATI, HIPOKSIK ISKEMIK)

ABSTRACT

In spite of major advances in monitoring technology and knowledge of fetal and neonatal pathologies, perinatal asphyxia, hypoxic-ischemic encephalopathy (HIE), remains a serious condition causing significant mortality and long-term morbidity. Brain hypoxia and ischemia from systemic hypoxemia and reduce CBF are the primary triggering events for HIE, treatment of seizure is an essential component of management. No specific therapy for HIE. Accurate prediction of long-term complications is difficult.

ABSTRAK

Walaupun telah banyak dicapai kemajuan  teknologi di bidang teknologi monitoring dan patofisiologi perinatal asfiksia pada janin dan neonatus, Ensefalopati hipoksik iskemik masih merupakan  penyebab mortalitas dan morbiditas jangka panjang.

Ensefalopati hipoksik iskemik terutama  di picu oleh keadaan hipoksik otak, iskemik oleh karena hipoksik sistemik dan penurunan aliran darah ke otak. Tidak terdapat terapi spesifik pada ensefalopati hipoksik iskemik.

Kata kunci : Hypoxic Ischaemic Encephalophaty

Anoksia adalah istilah yang menunjukkan akibat tidak adanya suplai oksigen yang disebabkan oleh beberapa sebab primer. Hipoksia merupakan istilah yang menggambarkan turunnya konsentrasi oksigen dalam darah arteri, sedangkan iskemia menggambarkan penurunan aliran darah ke sel atau organ yang menyebabkan insufisiensi fungsi pemeliharaan organ tersebut.

Hypoxic ischaemic encephalopathy (HIE) merupakan penyebab penting kerusakan permanen sel-sel pada Susunan Saraf Pusat (SSP), yang berdampak pada kematian atau kecacatan berupa palsi cerebral atau defisiensi mental. (1)Angka kejadian HIE berkisar 0,3-1,8%. Australia (1995), angka kematian antepartum berkisar 3,5/1000 kelahiran hidup, sedangkan angka kematian intrapartum berkisar 1/1000 kelahiran hidup, dan angka kejadian kematian masa neonatal berkisar 3,2/1000 kelahiran hidup. Apgar Score 1-3 pada menit pertama terjadi pada 2,8% bayi lahir hidup dan AS 5 pada menit ke 5 pada 0,3% bayi lahir hidup. Lima belas hingga 20% bayi dengan HIE meninggal pada masa neonatal, 25-30% yang bertahan hidup mempunyai kelainan neurodevelopmental permanent (2).

Asfiksia perinatal adalah akibat berbagai kejadian selama periode perinatal yang menyebabkan penurunan bermakna aliran oksigen, menyebabkan asidosis dan kegagalan fungsi minimal 2 organ (paru, jantung, hati, otak, ginjal dan hematologi) yang konsisten.

Faktor-faktor resiko :

  1. Hipertensi selama kehamilan atau pre-eklampsia
  2. Restriksi pertumbuhan intra-uterin
  3. Terlepasnya plasenta
  4. Anemia fetus
  5. Postmaturitas
  6. Persalinan non fisiologis
  7. Malpresentasi termasuk vasa previa

Etiologi (3):

Hipoksia pada fetus disebabkan

  1. Oksigenase yang tidak adekuat dari darah maternal yang disebabkan hipoventilasi selama proses pembiusan, CHD, gagal nafas, keracunan CO2
  2. Tekanan darah ibu yang rendah karena hipotensi akibat dari anestesi spinal atau tekanan uterus pada vena cava dan aorta.
  3. Relaksasi uterus kurang karena pemberian oksitosin berlebihan akan menyebabkan tetani.
  4. Plasenta terlepas dini
  5. Penekanan pada tali pusat atau lilitan tali pusat
  6. Vasokonstriksi pembuluh darah uterus karena kokain
  7. Insufisiensi plasenta karena toksemia dan post date

Deteksi bayi resiko tinggi untuk terjadi asphyxia perinatal :

Dikatakan hanya 50% bayi yang membutuhkan resusitasi pada saat persalinan dapat diprediksi dengan riwayat antenatal atau tanda klinis pada saat persalinan. Beberapa prediktor yang dapat digunakan untuk memprediksi Apgar Score yang rendah adalah :

  1. Penghitungan pergerakan fetus (sensitivitas 12-50%, spesifisitas 91-97%)
  2. Tes non-stress (sensitivitas 14-59%, spesifisitas 79-97%)
  3. Profil biofisikal fetus
  4. Kelainan detak jantung janin (sensitivitas 31%, spesifisitas 93%)
  5. pH darah fetus (pH menurun sensitivitas 31%, pH meningkat spesifisitas 93%)
  6. Penurunan volume amnion
  7. Adanya mekoneum dalam amnion

Insufisiensi plasenta mungkin tidak terdeteksi pada pemeriksaan klinis.

Adanya hipoksia kronis intrauterin menyebabkan retardasi pertumbuhan fetus tanpa tanda-tanda distress fetal (misalnya bradikardia). Doppler umbilical waveform velocimetry (yang memperlihatkan tahanan vaskuler fetus) dan cordocentesis (menggambarkan hipoksia fetus) dapat digunakan untuk mendeteksi hipoksia kronik fetus. Kontraksi uterus menimbulkan penurunan konsentrasi oksigen, depresi sistim kardiovaskuler dan CNS dan menyebabkan Apgar Score rendah dan hipoksia post-natal di ruang persalinan.

Setelah lahir, hipoksia dapat disebabkan :

  1. Anemia berat karena perdarahan atau penyakit hemolitik.
  2. Renjatan akan menurunkan transport oksigen ke sel-sel penting disebabkan oleh infeksi berat, kehilangan darah bermakna dan perdarahan intrakranial atau adrenal.
  3. Defisit saturasi oksigen arterial karena kegagalan pernafasan bermakna dengan sebab defek serebral, narkosis atau cedera.
  4. Kegagalan oksigenasi karena CHD berat atau penyakit paru.

Patofisiologi dan patologi :

Beberapa menit setelah fetus mengalami hipoksia total, terjadi bradikardia, hipotensi, turunnya curah jantung dan gangguan metabolik seperti asidosis respiratorius. Respon sistim sirkulasi pada fase awal dari fetus adalah peningkatan aliran pintas melalui duktus venosus, duktus arteriosus dan foramen ovale, dengan tujuan memelihara perfusi dari otak, jantung dan adrenal, hati, ginjal dan usus secara sementara

Patologi hipoksia-iskemia tergantung organ yang terkena dan derajat berat ringan hipoksia. Pada fase awal terjadi kongesti, kebocoran cairan intravaskuler karena peningkatan permeabilitas dinding pembuluh darah dan pembengkakan sel endotel merupakan tanda nekrosis koagulasi dan kematian sel. Kongesti dan petekie tampak pada perikardium, pleura, timus, jantung, adrenal dan meningen. Hipoksia intrauterin yang memanjang dapat menyebabkan PVL dan hiperplasia otot polos arteriole pada paru yang merupakan predesposisi untuk terjadi hipertensi pulmoner pada bayi. Distres nafas yang ditandai dengan gasping, dapat akibat aspirasi bahan asing dalam cairan amnion (misalnya mekonium, lanugo dan skuama)(4).

Kombinasi hipoksia kronik pada fetus dan cedera hipoksik-iskemik akut setelah lahir akan menyebabkan neuropatologik khusus dan hal tersebut tergantung pada usia kehamilan. Pada bayi cukup bulan akan terjadi nekrosis neuronal korteks (lebih lanjut akan terjadi atrofi kortikal) dan cedera iskemik parasagital. Pada bayi kurang bulan akan terjadi PVL (selanjutnya akan menjadi spastik diplegia), status marmoratus basal ganglia dan IVH. Pada bayi cukup bulan lebih sering terjadi infark fokal atau multifokal pada korteks yang menyebabkan kejang fokal dan hemiplegia jika dibandingkan dengan bayi kurang bulan. Identifikasi infark terbaik dilakukan dengan CT Scan atau MRI. Edema serebral menyebabkan peningkatan tekanan intrakranial, dan sering terjadi pada HIE berat. Excitatory asam amino mempunyai peran penting dalam patogenesis cedera asfiksia otak (5)

Manifestasi klinis :

Tanda hipoksia pada fetus dapat diidentifikasi pada beberapa menit hingga beberapa hari sebelum persalinan. Retardasi pertumbuhan intrauterin dengan peningkatan tahanan vaskular merupakan tanda awal hipoksia fetus. Penurunan detak jantung janin dengan variasi irama jantung juga sering dijumpai. Pencatatan detak jantung janin secara terus menerus memperlihatkan pola deselerasi yang bervariasi atau melambat dan analisa darah dari kulit kepala janin menunjukkan pH<7,2. Asidosis terjadi akibat komponen metabolik atau respiratorik. Terutama pada bayi menjelang aterm, tanda-tanda hipoksia janin merupakan dasar untuk memberikan oksigen konsentrasi tinggi pada ibu dan indikasi untuk segera mengakhiri kehamilan untuk mencegah kematian janin atau kerusakan SSP

Pada saat persalinan, air ketuban yang berwarna kuning dan mengandung mekoneum dijumpai pada janin yang mengalami distres. Pada saat lahir, biasanya terjadi depresi pernafasan dan kegagalan pernafasan spontan. Setelah beberapa jam kemudian, bayi akan tampak hipotonia atau berubah menjadi hipertonia berat atau tonus tampak normal.

Derajat encephalopathy dibagi 3, secara keseluruhan resiko terjadi kematian atau kecacatan berat tergantung pada derajat HIE.

  1. Derajat 1 : 1,6%
  2. Derajat 2 : 24%
  3. Derajat 3 : 78%
  4. Ensefalopati >6 hari pada derajat 2 juga mempunyai resiko tinggi terjadi kecacatan neurologi berat.

Kelainan EEG digolongkan menjadi 3 yang masing-masing menunjukkan angka rata-rata kematian atau kecacatan berat :

  1. Kelainan berat (burst suppression, low voltage atau isoelektrik)          : 95%
  2. Kelainan sedang (slow wave activity)                                      : 64%
  3. Kelainan ringan atau tanpa kelainan                                                       : 3,3%

Tabel 1 :Gradasi HIE pada bayi cukup bulan

Tanda klinis Derajat 1 Derajat 2 Derajat 3
Tingkat kesadaran

 

Tonus otot

Postur

Refleks tendon/klonus

Myoclonus

Refleks Moro

Pupil

Kejang

EEG

Durasi

Hasil akhir

Iritabel

 

Normal

Normal

Hiperaktif

Tampak

Kuat

Midriasis

Tidak ada

Normal

<24 jam

Baik

Letargik

 

Hipotonus

Fleksi

Hiperaktif

Tampak

Lemah

Miosis

Sering terjadi

Voltage rendah yang berubah dengan kejang

24 jam – 14 hari

bervariasi

Stupor, coma

 

Flaksid

Decerebrate

Tidak ada

Tidak tampak

Tidak ada

Tidak beraturan, refleks cahaya lemah

Decerebrate

Burst suppression to isoelektrik

Beberapa hari hingga minggu

Kematian, kecacatan berat

Pucat, sianosis, apnea, bradikardia dan tidak adanya respon terhadap stimulasi juga merupakan tanda-tanda HIE. Cerebral edema dapat berkembang dalam 24 jam kemudian dan menyebabkan depresi batang otak. Selama fase tersebut, sering timbul kejang yang dapat memberat dan bersifat refrakter dengan pemberian dosis standar obat antikonvulsan. Walaupun kejang sering merupakan akibat HIE, kejang pada bayi juga dapat disebabkan oleh hipokalsemia dan hipoglikemia (6,7).

Sebagai tambahan, disfungsi SSP, gagal jantung kongesti dan syok kardiogenik, hipertensi persisten pulmonary, sindroma distress nafas, perforasi gastrointestinal, hematuria dan nekrosis tubular akut sering terjadi bersama dengan asfiksia pada masa perinatal.

Setelah persalinan, hipoksia yang terjadi biasanya disebabkan karena gagal nafas dan insufisiensi sirkulasi.

Pemeriksaan penunjang lain :

Pemeriksaan CT scan, MRI relatif tidak sensitif pada fase awal, dikatakan pemeriksaan tersebut bermanfaat untuk menegakkan diagnosis struktural pada fase lanjut dan pemeriksaan tersebut tidak rutin dilakukan.

  1. Kelainan USG: Dapat mendeteksi perdarahan. USG kurang baik untuk mendeteksi kerusakan kortikal. Lesi baru terlihat setelah 2-3 hari terjadi kelainan.
  2. CT Scan: Hipodensitas baru tampak setelah 10-14 hari terjadi kelainan. Resiko terjadi kematian atau kecacatan neurologi berat berkisar 82% pada bayi yang memperlihatkan hipodensitas berat atau perdarahan berat
  3. Nuclear magnetic resonance: Dapat memperlihatkan struktur otak dan fungsinya dan sangat sensitif untuk memprediksi prognosis penyakit
  4. Somatosensory evoked potential: terdapat hubungan erat antara hasil akhir dengan SEP. Bayi dengan hasil akhir normal juga mempunyai hasil SEP yang normal pada usia < 4 hari, sebaliknya bayi dengan SEP abnormal pada usia < 4 hari akan mempunyai kelainan pada pengamatan di usia selanjutnya.

Pemeriksaan penunjang lain :

Pemeriksaan CT scan, MRI relatif tidak sensitif pada fase awal, dikatakan pemeriksaan tersebut bermanfaat untuk menegakkan diagnosis struktural pada fase lanjut dan pemeriksaan tersebut tidak rutin dilakukan.

  1. Kelainan USG: Dapat mendeteksi perdarahan. USG kurang baik untuk mendeteksi kerusakan kortikal. Lesi baru terlihat setelah 2-3 hari terjadi kelainan.
  2. CT Scan: Hipodensitas baru tampak setelah 10-14 hari terjadi kelainan. Resiko terjadi kematian atau kecacatan neurologi berat berkisar 82% pada bayi yang memperlihatkan hipodensitas berat atau perdarahan berat
  3. Nuclear magnetic resonance: Dapat memperlihatkan struktur otak dan fungsinya dan sangat sensitif untuk memprediksi prognosis penyakit
  4. Somatosensory evoked potential: terdapat hubungan erat antara hasil akhir dengan SEP. Bayi dengan hasil akhir normal juga mempunyai hasil SEP yang normal pada usia < 4 hari, sebaliknya bayi dengan SEP abnormal pada usia < 4 hari akan mempunyai kelainan pada pengamatan di usia selanjutnya.

Terapi :

Terapi bersifat suportif dan berhubungan langsung dengan manifestasi kelainan sistim organ. Tetapi hingga saat ini, tidak ada terapi yang terbukti efektif untuk mengatasi cedera jaringan otak, walaupun banyak obat dan prosedur telah dilakukan (Martin AA, 1995 (5). Fenobarbital merupakan obat pilihan keluhan kejang yang diberikan dengan dosis awal 20mg/kg dan jika diperlukan dapat ditambahkan 10mg/kg hingga 40-50mg/kg/hari intravena. Fenitoin dengan dosis awal 20mg/kg atau lorazepam 0,1mg/kg dapat digunakan untuk kejang yang bersifat refrakter. Kadar fenobarbital dalam darah harus dimonitor dalam 24 jam setelah dosis awal dan terapi pemeliharaan dimulai dengan dosis 5mg/kg/hari. Kadar fenobarbital yang berfungsi terapeutik berkisar 20-40mg/mL.

Pada beberapa percobaan dengan hewan dan manusia ditemukan keuntungan dalam hubungannya dengan hasil akhir neurologi. Cara yang digunakan disebut selective cerebral cooling yang menggunakan air dingin disekitar kepala. Penelitian lanjutan masih dibutuhkan untuk dapat merekomendasikan pengobatan ini khususnya pada bayi.

Allopurinol pada bayi prematur ternyata tidak mempunyai manfaat dalam menurunkan insiden periventrikuler leukomalasia. Dikatakan pada hewan coba, allopurinol mempunyai peranan sebagai additive cerebral cooling sebagai neuroprotektor. Penelitian lanjutan masih dibutuhkan untuk merekomendasikan penggunaan allopurinol pada neonatus dengan HIE.

Penggunaan steroid pada percobaan hewan tidak mempunyai manfaat menurunkan cedera otak. Pada serial kasus yang dilaporkan, steroid hanya menurunkan tekanan intra kranial secara temporer dan tidak memperbaiki hasil akhir penderita dengan HIE.

Prognosis :

Prognosis tergantung pada adanya komplikasi baik metabolik dan kardiopulmoner yang dapat diterapi, usia kehamilan dan beratnya derajat HIE. Apgar score rendah pada 20 menit pertama, tidak adanya pernafasan spontan pada 20 menit pertama dan adanya tanda kelainan neurologi yang menetap pada usia 2 minggu dapat digunakan sebagai faktor untuk memprediksi kemungkinan kematian atau defisit neurologi baik kognitif maupun motorik yang berat. Mati otak yang terjadi setelah diagnosis HIE ditegakkan berdasarkan penurunan kesadaran berat (koma), apnea dengan PCO2 yang meningkat dari 40 hingga >60 mmhg dan hilangnya refleks batang otak (pupil, okulocephalic, oculovestibular, kornea, muntah dan menghisap). Gejala klinis tersebut ditunjang dengan hasil EEG (1)

KEPUSTAKAAN

  1. Cordes I, Roland EH, Lupton BA, et al. Early prediction of the development of microcephaly after hypoxic-ischaemic encephalopathy in the full term newborn. Pediatrics 1994.,93 :703
  2. Ekert P, Perlman M, Steilin M, et al. Predicting the outcome of postasphyxial hypoxic-ischaemic encephalopathy within 4 hours of birth. J Pediatr 1997 .,131 :613
  3. Bager B. Perinatally acquired brachial plexus Palsy a persisting challenge. Acta Pediatr 1997.,86 :1214
  4. Martin – Ancel A, Gracia-Alix A, et al. Multiple organ involvement in perinatal asphyxia. J Pediatr 1995., 127 ;786
  5. Evans D, Levene M. Neonatal seizures. Arch Dis Child 1998.,78 :F70
  6. Hall RT, Hall FK, Daily DK. High-dose Phenobarbital therapy in term-infants with severe perinatal asphyxia: A randomised, prospective study with three-years follow-up. J Pediatr 1998.,132 :345
  1. Perlman JM, Risser R, Broyles RS. Bilateral cystic periventricullar leucomalacia in the premature infants: Associated risk factors. Pediatrics 1998.,97 :822
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