Medical treatment of severe ovarian hyperstimulation syndrome 重度卵巢过度刺激综合征的药物治疗方案

Patients with severe ovarian hyperstimulation syndrome (OHSS) should be evaluated to determine if the meet the criteria for admission to the hospital, in particular if they present with shortness of breath or diminished urine output or abdominal pain. The medical management relies on the restoration of the intravascular volume to assist with renal perfusion as well as preventing thromboembolism.

患者如有发生严重的卵巢过度刺激综合征(OHSS)，医生应当评估其是否符合住院标准，特别需要评估患者是否有呼吸窘迫、少尿或者腹痛的症状。对患者的药物治疗主要依靠恢复血管内血容量的途径，以提高肾脏血流灌注，预防血栓形成。

Correction of circulatory volume

恢复血流量

The main line of treatment is correction of the circulatory volume and electrolyte imbalance. Several authors have described fluid management protocol for patient presenting with severe OHSS. At the Johns Hopkins Hospital, all the patients admitted with OHSS are initially treated with 1L of normal saline over one hour (1). Lactated Ringer solution (Hopkins protocol) is not recommended because many of the OHSS patients tend to be hyponatremic. If the patient has a satisfactory urine output in response to the fluid bolus, at least 50 mL over the hour after the fluid bolus, an IV fluid maintenance protocol is initiated. Typically 5% dextrose in normal saline is infused at 125-150 mL per hour and urine output is assessed every four hours. Hematocrit is determined four to six hours after the start of IV hydration to insure that hemoconcentration is corrected. If there is inadequate response in the urine output from the initial 1 L fluid bolus, IV crystalloid fluids are stopped and a regimen of low volume hyperosmolar IV therapy is begun. An IV infusion of 200 mL of 25% albumin solution is given over four hours and the hematocrit is rechecked until it is 36%-38%.

治疗的首要目标是恢复血流量和解决电解质紊乱的问题。有几位研究人员描述了通过流体药物治疗院中OHSS患者的方案。在约翰霍普金斯医院，所有住院的OHSS患者最开始都用1L生理盐水治疗超过一个小时(1)。由于许多OHSS患者容易患有低钠血症，因此不推荐使用乳酸林格溶液(霍普金斯方案)。如果患者在生理盐水滴注后尿量达标，即在滴注后1小时内尿量至少有50mL，则可以开始静脉滴注维持方案。生理盐水中含有5%的葡萄糖，通常会以每小时125-150mL的速度输入，需要每四个小时检测一次尿量。在静脉滴注开始后四到六小时内需检测血细胞比容，以确保血液浓缩得以纠正。如果在滴注1L生理盐水后尿量反应不足，应当停止生理盐水滴注，改为使用低容量高渗透液体滴注方案，可以在四小时内用静脉滴注200mL 25%的白蛋白溶液，并重新检查血细胞比容直至达到36%-38%。

Albumin, dextran, mannitol, and hydroxyethyl starch have been used for the management of severe OHSS (2). Hydroxyethyl starch has the advantage of a non-biological origin and a high molecular weight of 200-1000 Kda versus 69 Kda for albumin. Abramov et al. (3) compared the efficacy of hydroxyethyl starch with albumin in 16 patients. They observed higher urine output, fewer paracenteses, and shorter hospital stays with hydroxyethyl starch. Gamzu et al. (4) compared hydroxyethyl starch and Haemaccel and found no clinical advantage for the hydroxyethyl starch.

白蛋白，葡聚糖，甘露醇和羟乙基淀粉也被用于治疗重度过度刺激综合征(2)。羟乙基淀粉具有非生物来源和高分子量的优点。它的分子量是200-1000Kda，而白蛋白的分子量为69Kda。Abramov等人(3)比较了16位患者使用羟乙基淀粉与白蛋白后的结果，发现使用羟乙基淀粉的患者尿量更多，腹腔穿刺次数更少，住院时间更短。Gamzu等人(4)比较了羟乙基淀粉和尿素交联明胶，但没有发现使用羟乙基淀粉的优势。

Hyponatremia and hyperkalemia

低钠血症和高钾血症

Electrolyte imbalances are frequently encountered in cases of severe OHSS. Appropriate electrolyte solutions should be used and restriction of salt and water is not recommended. Hyperkalemia may be associated with cardiac arrhythmias, and thus acute management may involve treatment that transfers potassium into the intracellular space such as with insulin, glucose, and sodium bicarbonate, and to protect the heart from elevated potassium levels such as with calcium gluconate, as recommended by the ASRM Practice Committee. Electrocardiagraphic manifestations of cardiac arrhythmias include prolonged PR and QRS intervals, ST segment depression, and tall peak T waves. These indicate the immediate need for treatment with calcium gluconate. Cation exchange removes potassium from the body but its onset of action is one to two hours. It may be administered orally, or rectally as a retention enema.

重度OHSS患者经常伴有电解质紊乱的症状。应使用适当的电解质溶液进行治疗，不建议限制盐和水摄入。高钾血症可能会导致心律失常，按照美国辅助生殖协会的操作指导，紧急情况下可以用胰岛素，葡萄糖或碳酸氢钠等将钾转移到细胞内部，避免心脏受到高钾水平的影响。心律失常在心电图上的表现包括PR和QRS间接延长，ST段压低和T波高，需要马上用葡萄糖酸钙进行治疗。阳离子交换疗法可以将钾从体内去除，但在用药后一到两个小时才开始起作用，可以通过口服给药，也可以通过灌肠给药。

Diuretics

利尿剂

Diuretics therapy without prior volume expansion may precipitate intravascular coagulation. Lasix is used in patients with pulmonary edema. Some authors have recommended albumin/Lasix chase for the management of patients with severe OHSS (5).

使用利尿剂前，需要先增加血流量，否则可能会导致血管内凝血。呋塞米适用于肺水肿患者。一些研究人员推荐用白蛋白/呋塞米联合法治疗重度OHSS患者(5)。

Thromboembolism

血栓栓塞

Thromboembolism is the most dangerous complication of OHSS. The majority of thromboembolic cases are venous in origin. Most of the serious complications, however, arise from arterial thromboses. The timing of arterial and venous thrombosis in OHSS patients differed. Arterial events usually occurred concurrently with the onset of OHSS whereas venous thromboses may occur several weeks after the clinical resolution of OHSS.

血栓栓塞是OHSS最危险的并发症。大多数血栓栓塞病例起源于静脉血栓。然而，大多数严重的并发症起源于动脉血栓。OHSS患者动脉和静脉血栓形成的时间不同。动脉血检通常与OHSS临床症状同时发生，而静脉血栓可能在OHSS症状消退后数周才发生。

Patients with severe OHSS should be started on subcutaneous heparin, 5000 units twice daily, or Lovenox, 40 mg subcutaneously, immediately on admission to the hospital and this regimen should continue throughout the hospital stay (6). Prophylactic doses of anticoagulants should also be considered for patients who develop moderate and severe OHSS even if they are treated as outpatients (6). This treatment should be maintained for an extended period of one to two months beyond the clinical resolution of OHSS.

重度OHSS患者应在住院后立即开始皮下注射肝素，每天2次，每次5000单位，或皮下注射依诺肝素40mg，一直到患者出院(6)。对于中度和重度OHSS患者，即使他们接受门诊治疗，也应考虑给他们预防性剂量的抗凝剂进行治疗(6)，直至OHSS临床症状消退后一至两个月后。

References

参考文献

1. Whelan JG, Vlahos NF. The ovarian hyperstimulation syndrome. Fertil Steril 2000; 73: 883-896.

2. Badawy SZA, Rizk B. Controlled ovarian stimulatioin in difficult cases. Sex Reprod Menopause 2011; 9: 17-23.

3. Abramov Y, Fatum M, Abrahamov D, Schenker JG. Hydroxyethylastarch versus human albumin for the treatment of severe ovarian hyperstimulation syndrome: a preliminary report. Fertil S2001;75： 1228-1230.

4. Gamzu R, Almog B, Levin Y, et al. Efficacy of Hydroxyethyl starch and Haemaccel for the treatment of severe ovarian hyperstimulation syndrome. Fertil Steril 2002; 77:1302-1303.

5. Rizk B, Aboulghar MA. Classification, pathophysiology and management of ovarian hyperstimulation syndrome. In: Brinsden P ed. Textbook of In-vitro Fertilization and Assisted Reproduction. 2nd edn. Canforth, UK: Parthenon. 1999; 131-155.

6. Chan WS. The ‘ART’ of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology. Curr Opin Obstet Gynecol 2009; 21: 207-218.