@2024 Afarand., IRAN

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ISSN: 2251-8215    Sarem Journal of Reproductive Medicine 2017;1(4):145-152

Background
Ovarian Hyper stimulation syndrome (OHSS) is often an iatrogenic disorder of assistant reproductive ‎treatment (ART), which can be followed by a controlled ovarian hyper stimulation (COH) following ‎human chorionic gonadotropin (hCG) injection ... [1].‎
Previous Studies
‎... [2, 3]. Because this syndrome is a major complication of ART therapies and IVF procedures, doing ‎basic preventive measures before the start of the IVF program for those who are likely to develop this ‎syndrome and providing secondary preventive measures for patients who during the ovarian ‎stimulation period treatment has been shown to cause excessive response symptoms has been ‎suggested [4].‎ The extreme displacement of body fluids is a pathophysiologic phenomenon of OHSS, leading to ‎ascites and pulmonary effusion. Researchers have long believed that fluid displacement is due to ‎increased capillary permeability [5]. ... [6-17].‎ Prevention of OHSS syndrome is possible by pharmacological and non-pharmacological methods. ‎Suggested drug treatments include albumin or hydroxyethyl starch infusion and dopamine agonist ‎therapy [4, and 13].‎ ‎... [17-23].At the time of the initiation of the present study, the first-line drug introduced in the resource ‎was for the treatment of OHSS cases was albumin. Access to albumin at a specific time in Iran was ‎severe. Therefore, based on pathophysiology of the disease and the pharmacological properties of ‎drugs, mannitol as an alternative to treatment (albeit with different mechanisms) was applied ... [24-‎‎30].‎
Aim(s)
In the present study, the ovarian overstimulation syndrome management with combination protocols, ‎including preventive action and treatment with mannitol, was considered. The purpose of this study ‎was to evaluate the effectiveness of mannitol in the management of moderate and severe OHSS.‎
Research type
This research is a non-experimental intervention.‎
Research society, place and time
This research was performed for 19 years on moderate and severe degrees of OHSS patients in the time ‎intervals of 1994-2005 Sarem Medical Center and then in Sarem Women Specialized Hospital from ‎‎2005 to 2013.‎
Sampling method and number
During this period, 6970 women who had been nominated for IVF and entered the ovarian stimulation ‎protocol were examined.‎
Used devices&materials
In order to design an appropriate and complete research project, the researchers presented the results ‎and documentation of the initial desirable outcome of the primary compulsory pilot study to the ‎Ethics Committee of the Center for Medical Education. The committee, after conducting the necessary ‎examinations, authorized the launch of an interventional study during the license No. 04-3263 dated ‎‎3/19/1995.‎ A mild type of ovarian overstimulation syndrome does not require any intervention [13, 30]. ‎Therefore, only moderate and severe degrees of OHSS syndrome patients entered this study. During the ‎preparation of patients for the IVF process and after initiation of the stimulation, sonography ‎monitoring of the ovaries was placed on the agenda of the infertility clinic. All patients with more than ‎‎14 follicles larger than 14 mm were considered to be at risk for OHSS and underwent mannitol drug ‎treatment. In this group, the prediction of the severity of OHSS syndrome was based on the protocol ‎‎(Table 1).‎ The basis of this thought was the dependence of this syndrome on the level of serum estradiol and the ‎fact that each follicle produce at least 200 pg of estrogen per ml of serum of the patient. Accordingly, in ‎this categorization, the approximate level of 2800-4000 pg/ ml serum estrogen was considered as the ‎risk of moderate OHSS and estrogen levels greater than 4000 g /ml was considered as a risk of severe ‎OHSS [31]. If, contrary to the prevention, the patients showed symptoms of ovarian overstimulation ‎syndrome, they were entered into the study according to the categorization of Rizk and Aboulghar [13].‎Patient monitoring: After the start of treatment and during treatment with mannitol, certain ‎laboratory parameters, vital signs and clinical examinations were monitored on a daily basis and ‎recorded in the patient's records.‎ Contraindications to mannitol include allergic reaction, acute renal disease (anorexia), acute ‎dehydration, intracranial hemorrhage, progressive heart failure, renal insufficiency after mannitol ‎therapy, congestion or pulmonary edema. It is recommended that the medicine should not be used to ‎ensure adequate kidney function and proper urinary flow. It is recommended to first evaluate one to ‎two kidney responses. Clinical monitoring and dosing of the drug over the entire infusion time, ‎electrolyte control and correction of the electrolytes if necessary, and serum osmolality adjustment ‎less than 300-300 mOsm / L3 to minimize the side effects of the drug are recommended. Possibility of ‎damage or tubular necrosis is high at high concentrations and consistent with the use of other ‎nephrotoxic drugs, sepsis or the presence of diseases of the kidney [28].‎ Mannitol drug side effects include chest pain, congestive heart failure (CHF), circulatory overload, ‎changes in blood pressure (up or down), peripheral edema and palpitations, tremor and cold fever, ‎seizure, dizziness, fever, headache, nausea and vomiting. In the case of daily administration of more ‎than 200 grams of mannitol per day, the increase in serum osmolality of more than 320 mOsm/L or ‎the osmolality gap of more than 50mOsm/L is associated with acute renal failure and tubular necrosis. ‎Mannitol infusion can also lead to electrolyte imbalance, dehydration, secondary hypovolemia to rapid ‎diuresis, hyperglycemia, hypernatremia, hyponatremia, hyperkalemia due to hyper osmolality, ‎metabolic acidosis, increased osmolality and water poisoning [28]. These drug complications, ‎especially in cases that overlap with the complications of the OHSS syndrome, create special ‎complexity and require more careful monitoring of the patient.‎ During mannitol therapy, if symptoms of shortness of breath, tachycardia, sweating, reduction of Out-‎put, and muscle cramps were observed in the patient, the dose of mannitol was reduced (BID to daily ‎or daily to DC).‎ Due to controlling the probability of embolism in patients, D. Dimer's lab test was also added to the ‎patient's test suite in the final year of the study. This test is performed only on the first day of ‎treatment and after the end of the drug infusion.‎ In order to calculate the osmolality gap and for the patient's higher immunity, serum osmolality ‎measurements were added to the set of monitoring methods during treatment in the last months of the ‎study.‎ Monitoring parameters were renal function monitoring, daily control of fluid inlet and outlet, serum ‎osmolality and osmolality gap. ... [28, 32].‎ Administering Mannitol IV: According to the Executive Committee of the American Society for ‎Reproductive Medicine, the first priority in OHSS management is the correction of hypovolemia, ‎hypotension and oliguria. This reference, in the management of fluids in OHSS patients, recommends ‎rapid hydration of the patient's body with intravenous fluids (500 to 100 milliliters), and the fluid ‎should be carefully adjusted to improve urination output (urine output≥20-30 ml/h) And correction of ‎blood concentrations in the patient (dextrose 5% or saline 0.9%). This reference also recommends the ‎use of salt candy serum (5% dextrose in normal saline) due to control of hyponatremia to the lactated ‎ringer's serum. In this study, Mannitol has been also referred to besides albumin and plasma "fresh ‎frozen plasma" as a Plasma expander for fluid management in OHSS patients [21].‎ Mannitol therapy method was developed based on this basis and also on the basis of mannitol ‎consumption dose for ICP, cerebral edema and ICP increase.‎ ‎1) Mannitol therapy was performed with 500 ml mannitol 20% solution daily or twice a day ‎‎(equivalent to 100 to 200 g mannitol per day). The dose of Mannitol has been considered to be within ‎the range of 1.0-5.1 g / kg / dose, depending on the clinical condition and severity of the symptoms ‎‎(ICP: 0.20-1.0 g / kg / dose, and IOP: 0.25-2.0 g / kg / dose) [28].‎ ‎2) Each 500 milliliters of mannitol, 20% plus 500 ml of sugar-salt solution (dextrose 5%, saline 0.9%) ‎was infused through Y-site for 4 hours to provide the 1,000 ml initial volume at the earliest time.‎ ‎3) Routine abdominal examinations, pulmonary sound, abdominal measurement, patient weight, ‎diuresis and blood concentrations were carried out in order to decide on the continuation of hydration. ‎If these examinations were acceptable, after 4 hours of infusion, 500 ml of solution of sugar and salt ‎was infused for 30 to 60 minutes; however, if the clinical examinations indicated the progression of ‎fluid retention in the patient's body, this infusion was not performed [21].‎ ‎4) During the treatment, urinary excretion was maintained at an acceptable level (Urine output ≥ 20-30 ‎ml / h) and mannitol therapy was continued until abdominal and pulmonary symptoms were ‎completely resolved. One of the indicators for improving the patient's recovery in management of ‎OHSS syndrome is the high total amount of fluid output from the patient's body (output) from the total ‎amount of intake of intake (Intake). This incident (Output> Intake) indicates the extra fluid flow out of ‎the body and the end of the water retention process in the patient's body, and the durability of this was ‎taken into account in precise monitoring to ensure control of the complications of the OHSS syndrome. ‎If, for a period of 24 hours, the total amount of fluid output from the patient's body was not greater than ‎the total amount of fluid intaking the body, the patient was undergone NPO, and the administration of ‎mannitol was done as a BID of 500 ml serum, and then 1000 ml of serum after each dose of mannitol ‎‎(instead of 500 milliliter mentioned in the section 3) were infused (selection of serum type was ‎according to clinical Notes 1 and 2). As the patient passed out of the amount of fluid entering his body, ‎the patient was withdrawn from the NPO order and returned to the previous (Daily) treatment. ‎ Clinical note 1: In case of diabetic patient, instead of glucose-salt serum (in Sections 2 and 3), normal ‎saline 0.9% solution was used. ‎ Clinical note 2: Based on the serum sodium level and in the case of hypernatremia, with the aim of ‎correcting and based on conditions, the sugar content (dextrose 5%) or Half saline was used instead of ‎glucose-salt (Section 2 and 3).‎ It takes 1 to 3 hours to initiate the effect of diuresis after mannitol injection. A half-life of 4.7 hours, a ‎very modest liver metabolism (converted to glucagon), and urinary excretion (55 to 87% unchanged) ‎have been recorded for mannitol. Its distribution to the external space is limited (except in very high ‎serum concentrations) and it does not have the ability to penetrate the cerebrospinal fluid [28].‎ Finally, the data of patients were analyzed by descriptive and analytical statistics using SPSS 19 ‎software.‎
Findings by Text
Of the 6970 patients, in the 19 year interval from 1994 to 2013, the total number of cases of OHSS was ‎‎1737 (24.92%). Of these, 1360 were Mild OHSS, equivalent to 78.30% of the total OHSS and 19.51% of ‎the total induction. The number of 338 patients (19.46% of OHSS cases and 4.85% of all induction ‎cases) were moderate and 39 cases (2.24% of cases of OHSS and 0.56% of total induction) had severe ‎type ovarian hyper stimulated syndrome. Of those with severe OHSS, 32 (1.84% OHSS cases) were of ‎severe A, 6 (0.34% OHSS cases), were of severe B and 1 (0.6% OHSS cases) was of severe type C. In ‎general, the number of candidate OHSS cases for intervention (moderate and severe) was 21.7% of all ‎OHSS cases (Table 2).‎Among OHSS individuals, 13.1% of the successful chemical pregnancy was obtained (in terms of ‎positive b-hCG test). There was no significant relationship with the incidence of pregnancy and ‎severity of OHSS (p=0.309; x2=2.346; df=2), so that the incidence of mild OHSS was 41% and in ‎moderate and severe types, it was 10 And 9.5% respectively.‎ The percentage of pregnancies (in terms of bhCG positive) among patients with different degrees of ‎OHSS was 13.1%. Pregnancy rates based on observing pregnancy sac (clinical pregnancy) was 12.6% ‎in the same group, that it was 13.5% for Mild cases and 9.4% and 9.5% for moderate and severe cases ‎respectively.‎ There was no significant relationship between BMI of patients and severity of OHSS (p=0.522; ANOVA-‎F=0.915; df =2).‎ ‎66.7% of the severe cases of OHSS had a primary diagnosis of ovarian infertility (OF); this amount had ‎the significant association with reduction in OHSS severity (p=0.0036; x2=11.266; df =2), so that in ‎cases with a moderate severity of 37.6%, the cases had a primary diagnosis of OF, and in Mild cases, ‎this was 32.8%. This was also true for the PCO record, so that 48.72% of severe OHSS cases had PCO ‎pre-diagnosis and 29.8% of the cases were moderate and 21.4% of the Mild cases had a history of PCO ‎that significant different was observed between the mentioned groups in this regard (p=0.0012, X 2 ‎‎=12.503; df=2). The total number of people with PCO among OHSS patients was 411 (23.66%).‎ There was no significant association between the number of previous pregnancies (among secondary ‎infertility cases) and number of delivery with OHSS severity (p<0.05).‎ In this study, analysis of the results of mannitol treatment was performed on moderate and severe ‎cases of OHSS. In describing this group of patients, the mean age was 29.66 ± 4.27 years. Among the ‎moderate and severe cases of OHSS, the cases of canceled ET were 90.7%. This amount for all OHSS ‎cases is 10.9%. The average number of follicles counted in these subjects (moderate and severe cases) ‎was 16.65 ± 5.46. The average number of transmitted embryos in non-canceled cases in the fertility ‎cycle (despite moderate or severe OHSS) was 2. 57 ± 0.53.‎ After mannitol treatment, the following results were obtained in comparing the patients with moderate ‎and severe OHSS severity before and after treatment. ‎ The mean weight loss before and after treatment with mannitol was 3.21 ± 6.22 kg (df = 365; t = -2.242, ‎t-test, paired t-test, p = 0.024), which had a significant difference.‎ In the last year of the study, the D-Dimer index was measured for 63 patients treated with mannitol ‎protocol and according to pharmacological recommendations and assessment of the probable ‎incidence of embolism. The mean D-Dimer was 0.51 ± 0.44 during treatment.‎ In the same period of time, Osmolality gap was evaluated on the staff agenda and the mannitol ‎treatment protocol at Sarem Hospital. The mean osmolality gap in these 63 patients was 13.76 ± 11.1 ‎‎(range from 0.17 to 41.54).‎ Among patients, 4% had severe oliguria. 28% had mild oliguria, and the rest (44.3%) had a good ‎urinary output. This amount after treatment reduced to 1.3 % of severe oliguria, 17.3% of mild ‎oliguria, which was significantly different from the previous values (p = 0.021). The mean 24-hour ‎urine I / O difference before treatment was -349.60 ± 1289.81 cc which reached to 641.80 ± 1032.54 cc ‎after treatment. The differences in these rates were statistically significant (df = 372; t = -2.843; paired ‎t-test; p = 0.009).‎ No cases of mortality occurred among patients treated with the proposed protocol of mannitol therapy ‎in these years (from 19 years from 1373 to 1392) and it was zero.‎ Two patients had severe OHSS complications, that in each, occurrence of a complete failure to observe ‎the protocol for treatment with mannitol was seen. In the first case, a 36-year-old woman was a ‎primary infertility who, after ovarian stimulation and the presence of moderate to severe symptoms of ‎OHSS, and lack of proper urinary output, had an embryo transfer in the same cycle, and was not ‎canceled. The protocol was not well done for this patient and the recommended amount of overdose of ‎mannitol was recommended (5000 mg / kg / day), which exceeded the limit and received a total of ‎‎1400 grams of mannitol per day for 7 days, while it should not exceed 1100 grams. Ultimately, dialysis ‎was performed for this patient, and after 3 days of admission, she recovered and the pregnancy did not ‎occur. The second case was a 24-year-old woman with primary infertility, with embryo transfer in ‎contrast to the symptoms of OHSS. Unlike having oliguria,she was treated with mannitol and received ‎about 1300 grams of mannitol in a total of 8 days (13 mannitol doses), which was more than allowed.‎ ‎-The mean hospitalization days was 4.72 ± 2.92 days (range 2 to 11 days). ‎- There was a discomfort situation in 21 patients with severe OHSS before treatment, which was ‎resolved after treatment.‎ ‎- Respiratory distress was seen in 7 cases of patients with severe OHSS before treatment, and after ‎treatment in all of them, the distress was resolved.‎
Main comparison to the similar studies
As far as we know, to date, no studies have been conducted on mannitol use to manage ovarian hyper ‎stimulation syndrome, and this is the first formal study on this issue. Although due to specific time ‎constraints and existing constraints, this research was conducted without control group and in form of ‎non-experimental, its extent due to the number of patients and the length of time is its merit.‎ At the center, given the prevalence of mannitol in patients at risk of OHSS, the prevalence of mild, ‎moderate and severe OHSS in the study population is lower than that reported in some sources. In a ‎RCT research by Dr. Saremi et al., The effectiveness of mannitol in preventing the onset of OHSS ‎syndrome has been confirmed [31].‎ Improvement of OHSS syndrome in patients in this study was significant by decreasing patient weight, ‎discomfort and respiratory distress before and after treatment.‎ Oliguria or anuria modification and urinary intake / outflow process as indicators of renal function ‎and patient's recovery index before and after treatment are significant. The occurrence of mannitol ‎diuretics and the establishment of acceptable digestion is a hallmark of the therapeutic goal of ‎improving the flow of fluid in the patient's body.‎ Hemoconcentration correction, reduction of hematocrit and hemoglobin before and after treatment is ‎available with mannitol. Although this is not statistically significant, it should be noted that in fixed ‎red blood cell volume, increased hematocrit is a sign of a decrease in plasma volume. When the size of ‎the red blood cell stays constant, the change in hematocrit cannot be due to the change in plasma ‎volume; however, the change in plasma volume should always be considered more than the reflection ‎reflected by hematocrit. This means that the rise of 2 numbers in hematocrit from 45 to 47% is 4 times ‎smaller than the real drop of 8% of the plasma volume. It is therefore very important to note that in the ‎treatment of a patient with OHSS, any increase in hematocrit, which reaches 54%, does not actually ‎reflect the severity of the plasma decline and thus the severity and severity of the disease. Similarly, ‎during a treatment, a small drop in hematocrit may indicate a significant increase in the progression of ‎treatment in increasing plasma volume. This is very important in monitoring a patient in a clinic [31].‎ The average D-Dimer measured for embolism prognosis is in safe range in the patients under the ‎treatment. ‎ The mean and maximum osmolality, as well as the mean and maximum of osmolality gap obtained ‎during mannitol administration, confirms dose safety and mannitol administration method, designed ‎in the protocol, and the measured values for them indicate a lack of accumulation of mannitol in the in ‎vessels and subsequently ensure that no complications is associated with this accumulation.‎ The average number of reported hospital admissions in this study was significantly lower than other ‎studies. A significant reduction in the cost of treatment, considering the reduction in hospital bed day ‎and the much lower cost of mannitol than related products (albumin and hydroxyethyl starch), can be ‎considered as one of the notable advantages of this protocol in managing OHSS syndrome.‎ Considering the significant number of patients with moderate and severe degrees of OHSS in this study ‎‎(377 patients), absence of mortality and only two cases of morbidity are the favorable results of this ‎study.‎
Suggestions
Performing complementary studies as RCT is recommended to compare the effectiveness of mannitol ‎with other available drugs and therapies.‎
Limitations

Conclusions
Treatment with mannitol with the described protocol is effective in managing moderate and severe ‎OHSS. Particularly in relation to the control of signs and symptoms of the disease, the main indicators ‎of control of patients' recovery, as well as mortality and morbidity are acceptable results.‎
Acknowledgments
We are grateful to Ms. Leila Zand Azad for the valuable work in completing the information required ‎for the study, as well as all the members of Sarem Research Center, a specialized expert and specialist ‎of Sarem Hospital and working associates in different parts of the hospital, including clinics, ‎admissions and emergency department.‎
Conflict of interest

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TABLES and CHARTS

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