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| ID | Type | Description | Link |
|---|---|---|---|
| MRTG-02-15-2022-Ansari | Other Grant/Funding Number | Foundation for Anesthesia Education and Research | |
| YIG-2020 | Other Grant/Funding Number | Society Obstetric Anesthesia and Perinatology |
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| Name | Class |
|---|---|
| Foundation for Anesthesia Education and Research | OTHER |
| Society for Obstetric Anesthesia and Perinatology | OTHER |
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Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. Up to 80% of PPH is caused by uterine atony, the failure of the uterine smooth muscle to contract and compress the uterine vasculature after delivery. Laboratory and epidemiological studies show that low extracellular and serum calcium levels, respectively, decrease uterine contractility. A pilot study performed by the investigators supports the hypothesis that intravenous calcium chloride is well tolerated and may have utility in preventing uterine atony. The proposed research will establish the relationship between uterine tone and calcium through a clinical trial with an incorporated pharmacokinetic and pharmacodynamic (PK/PD) study. In a randomized, placebo-controlled, double-blind trial, investigators will establish the effect of 1 gram of intravenous calcium chloride upon quantitative blood loss and uterine tone during cesarean delivery in parturients with high risk of uterine atony. Investigators will concurrently collect serial venous blood samples to measure calcium for PK/PD modeling in this pregnant study cohort. High-quality clinical research and development of novel therapeutics to manage uterine atony are critical to reduce the high maternal morbidity and mortality from PPH.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Calcium chloride | Experimental | 1 gram of calcium chloride in total volume 60mL with sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. This intervention occurs IN ADDITION TO standard care with oxytocin 2 unit bolus and infusion at 7.5 units per hour which begins immediately after fetal delivery. |
|
| Saline placebo | Placebo Comparator | 60mL sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. This intervention occurs IN ADDITION TO standard care with oxytocin 2 unit bolus and infusion at 7.5 units per hour which begins immediately after fetal delivery. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Calcium chloride | Drug | See arm description above |
| |
| Saline placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Quantitative Blood Loss | Standardized volumetric and gravimetric assessment of blood loss during cesarean. Note: will analyze all participants, but planned subgroup analysis will also occur excluding patients with non-atonic reasons for blood loss including hysterotomy extension, placental abruption, cervical or vaginal laceration, etc | measurement occurs at conclusion of operating room case |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Postpartum Hemorrhage | Postpartum hemorrhage was defined as quantitative blood loss > 1000 milliliters during operative course | operative course (within 4-6 hours of fetal delivery) |
| Number of Participants With Second Line Uterotonic Requirement |
| Measure | Description | Time Frame |
|---|---|---|
| Quantitative Blood Loss, Subgroup Quantitative Blood Loss (QBL, mL), Excluding Cases of Documented Non-atonic Bleeding | Pre-specified subgroup analysis of primary outcome: Because the proposed mechanism of calcium action-improving uterine contractility-was not expected to improve bleeding from causes such as hysterotomy extension or arterial bleeding, the trial was powered for a prespecified subgroup analysis excluding patients with nonatonic blood loss documented in the surgeon's operative report. Documented nonatonic bleeding was defined as presence in the surgeon's operative report narrative of any of the following: hysterotomy extension, hysterotomy types other than low transverse (eg classical, T- or J-shaped), invasive or abnormally adherent placenta, placental abruption, uterine rupture, bleeding from leiomyomas, grade 3 or 4 vaginal lacerations, or cervical lacerations. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jessica Ansari, MD | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Jessica Ansari | Pacifica | California | 94044 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33652161 | Background | Cole NM, Abushoshah I, Fields KG, Carusi DA, Robinson JN, Bateman BT, Farber MK. The interrater reliability and agreement of a 0 to 10 uterine tone score in cesarean delivery. Am J Obstet Gynecol MFM. 2021 May;3(3):100342. doi: 10.1016/j.ajogmf.2021.100342. Epub 2021 Feb 27. | |
| 37917943 | Result | Ansari JR, Yarmosh A, Michel G, Lyell D, Hedlin H, Cornfield DN, Carvalho B, Bateman BT. Intravenous Calcium to Decrease Blood Loss During Intrapartum Cesarean Delivery: A Randomized Controlled Trial. Obstet Gynecol. 2024 Jan 1;143(1):104-112. doi: 10.1097/AOG.0000000000005441. Epub 2023 Nov 3. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Calcium Chloride | 1 gram of calcium chloride in total volume 60mL with sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. |
| FG001 | Saline Placebo | 60mL sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Calcium Chloride | 1 gram of calcium chloride in total volume 60mL with sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. |
| BG001 | Saline Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Quantitative Blood Loss | Standardized volumetric and gravimetric assessment of blood loss during cesarean. Note: will analyze all participants, but planned subgroup analysis will also occur excluding patients with non-atonic reasons for blood loss including hysterotomy extension, placental abruption, cervical or vaginal laceration, etc | Posted | Median | Inter-Quartile Range | milliliters | measurement occurs at conclusion of operating room case |
|
Day of cesarean delivery (and study drug administration). Adverse events were assessed formally at the conclusion of the operating room course prior to transport to the recovery unit. The clinical anesthesiologist discussed all possible side effects with the patient prior to filling out a form. (Anesthesiologist and patient blinded to allocation).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Calcium Chloride | 1 gram of calcium chloride in total volume 60mL with sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| New or subjective worsening in nausea | Gastrointestinal disorders | Nausea | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jessica Ansari | Stanford | 650-723-5349 | jansari@stanford.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 24, 2021 | Feb 26, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D014593 | Uterine Inertia |
| D006473 | Postpartum Hemorrhage |
| ID | Term |
|---|---|
| D004420 | Dystocia |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D002122 | Calcium Chloride |
| ID | Term |
|---|---|
| D017610 | Calcium Compounds |
| D007287 | Inorganic Chemicals |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
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Double blind, placebo controlled randomized clinical trial with 1:1 allocation
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The patient, obstetrician, anesthesiologist, and clinical research staff will be blinded to the intervention. Drugs will be labeled only as "study drug"
| Drug |
see arm description above |
|
Yes/no: did the patient require treatment with methylergonovine, carboprost, and/or misoprostol for uterine atony |
| within 4 hours of delivery |
| Number of Patients With a Transfusion Requirement | Yes/no, if patient required transfusion of packed red blood cells prior to hospital discharge | 96 hours of delivery |
| Change in Hematocrit From Baseline | Measured pre-delivery hematocrit minus measured post-operative day 1 hematocrit. Correction factor of 3 hematocrit points per unit packed red blood cells transfused | 1 day |
| Total Oxytocin Bolus Requirement | Total dose oxytocin bolus during cesarean | Cesarean duration, within 4-6 hours of fetal delivery |
| Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery | Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, 2021). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus. | 7 minutes after fetal delivery, 5 minutes after initiating study drug infusion |
| Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery | Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, PMID 33652161). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus. | 12 minutes after fetal delivery, 10 minutes after initiating study drug infusion |
| Fluid Requirement | Total crystalloid required during cesarean delivery in mL | Operating room duration, usually 2 hours |
| Percent Change in Mean Arterial Pressure | Baseline mean arterial blood pressure recorded as average of first 6 mean arterial blood pressures recorded in operating room. Percent change calculated as measured mean arterial blood pressure minus baseline, divided by baseline. Reported here as the maximal decrease in mean arterial pressure. Repeated measures ANOVA reported in Statistical Analysis. | every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline |
| Percent Change in Heart Rate From Baseline | Baseline heart rate recorded as average of first 6 heart rates recorded in operating room. Percent change calculated as measured heart rate minus baseline, divided by baseline. Maximal % increase in heart rate reported here. Repeated measures ANOVA used to analyze overall trend in Statistical Analysis below. | every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline |
| Total Phenylephrine Requirement | Total phenylephrine in milligrams administered while in the operating room | Duration of operating room time, up to 240 minutes |
| Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium | Measured using an Abbott istat machine and CG8+ cartridge to determine venous blood gas ionized calcium levels | In the operating room prior to study drug administration (generally <30 minutes prior to fetal delivery and study drug administration) |
| Pharmacokinetics of Calcium Chloride - Peak Change in Ionized Calcium From 1 Gram of Calcium Chloride | Generated from a 2-compartment population pharmacokinetic model in NONMEM using serial venous blood gas ionized calcium concentrations. | At Tmax (conclusion of the 10-minute intravenous calcium chloride infusion |
| Pharmacodynamic Effect of Calcium Upon Uterine Tone NRS | Data were not collected. This measure required blood specimens to be obtained at the time of tone scores and this was not done. | Within 20 minutes of study drug administration |
| Calculated at conclusion of operating room case |
60mL sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Body Mass index (kg/m^2) | Mean | Standard Deviation | kg/m^2 |
|
| Gravida (n) | Number of prior pregnancies | Median | Inter-Quartile Range | pregnancies |
|
| Para | Number of prior pregnancies reaching 20 weeks and 0 days of gestation, regardless of the number of fetuses or the outcome | Median | Inter-Quartile Range | Prior pregnancies |
|
| Gestational age (completed weeks) | Median | Inter-Quartile Range | completed weeks |
|
| Advanced maternal age (n, %) | Defined as age of >35 years at delivery | Count of Participants | Participants |
|
| Hypertension from all causes (n, %) | Count of Participants | Participants |
|
| Preeclampsia (n, %) | Count of Participants | Participants |
|
| Diabetes, all causes (n, %) | Count of Participants | Participants |
|
| Asthma (n, %) | Count of Participants | Participants |
|
| Multiple gestation (n, %) | Count of Participants | Participants |
|
| Chorioamnionitis (n, %) | Count of Participants | Participants |
|
| Trial of Labor after Cesarean (TOLAC) (n, %) | Count of Participants | Participants |
|
| Indication: first stage arrest | Indication for cesarean delivery: failure of the first stage of labor (cervical dilation) | Count of Participants | Participants |
|
| Indication: second stage arrest | Indication for cesarean delivery: failure of the second stage of labor, also known as failure to descend. The cervical achieved full (10cm) dilation, but the fetus failed to descend with pushing to allow a vaginal delivery. | Count of Participants | Participants |
|
| Indication: fetal intolerance of labor | Indication for cesarean delivery: evidence of fetal distress with labor based upon analysis of the fetal heart tracing by the obstetrician. | Count of Participants | Participants |
|
| Indication: failed operative vaginal delivery | Count of Participants | Participants |
|
| Indication: maternal request | Count of Participants | Participants |
|
| Indication: other | Count of Participants | Participants |
|
| Maximum oxytocin dose in labor | Mean | Standard Deviation | milliunits per minute |
|
| Hours of oxytocin exposure during labor | Mean | Standard Deviation | hours |
|
60mL sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp.
|
|
|
| Secondary | Number of Participants With Postpartum Hemorrhage | Postpartum hemorrhage was defined as quantitative blood loss > 1000 milliliters during operative course | Posted | Count of Participants | Participants | operative course (within 4-6 hours of fetal delivery) |
|
|
|
|
| Secondary | Number of Participants With Second Line Uterotonic Requirement | Yes/no: did the patient require treatment with methylergonovine, carboprost, and/or misoprostol for uterine atony | Posted | Count of Participants | Participants | within 4 hours of delivery |
|
|
|
|
| Secondary | Number of Patients With a Transfusion Requirement | Yes/no, if patient required transfusion of packed red blood cells prior to hospital discharge | Posted | Count of Participants | Participants | 96 hours of delivery |
|
|
|
|
| Secondary | Change in Hematocrit From Baseline | Measured pre-delivery hematocrit minus measured post-operative day 1 hematocrit. Correction factor of 3 hematocrit points per unit packed red blood cells transfused | Posted | Median | Inter-Quartile Range | Percentage of hematocrit | 1 day |
|
|
|
|
| Secondary | Total Oxytocin Bolus Requirement | Total dose oxytocin bolus during cesarean | Note: institutional standard policy is a 2 unit oxytocin bolus at the time of fetal delivery, with additional boluses prn | Posted | Median | Inter-Quartile Range | units | Cesarean duration, within 4-6 hours of fetal delivery |
|
|
|
| Secondary | Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery | Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, 2021). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus. | Posted | Median | Inter-Quartile Range | units on a scale | 7 minutes after fetal delivery, 5 minutes after initiating study drug infusion |
|
|
|
|
| Secondary | Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery | Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, PMID 33652161). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus. | Posted | Median | Inter-Quartile Range | units on a scale | 12 minutes after fetal delivery, 10 minutes after initiating study drug infusion |
|
|
|
|
| Secondary | Fluid Requirement | Total crystalloid required during cesarean delivery in mL | Posted | Mean | Standard Deviation | milliliters | Operating room duration, usually 2 hours |
|
|
|
| Secondary | Percent Change in Mean Arterial Pressure | Baseline mean arterial blood pressure recorded as average of first 6 mean arterial blood pressures recorded in operating room. Percent change calculated as measured mean arterial blood pressure minus baseline, divided by baseline. Reported here as the maximal decrease in mean arterial pressure. Repeated measures ANOVA reported in Statistical Analysis. | Posted | Mean | 95% Confidence Interval | percent change | every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline |
|
|
|
|
| Secondary | Percent Change in Heart Rate From Baseline | Baseline heart rate recorded as average of first 6 heart rates recorded in operating room. Percent change calculated as measured heart rate minus baseline, divided by baseline. Maximal % increase in heart rate reported here. Repeated measures ANOVA used to analyze overall trend in Statistical Analysis below. | Posted | Mean | 95% Confidence Interval | percent change | every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline |
|
|
|
|
| Secondary | Total Phenylephrine Requirement | Total phenylephrine in milligrams administered while in the operating room | Total of documented phenylephrine bolus and infusion administration during operative course | Posted | Median | Inter-Quartile Range | milligrams | Duration of operating room time, up to 240 minutes |
|
|
|
| Secondary | Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium | Measured using an Abbott istat machine and CG8+ cartridge to determine venous blood gas ionized calcium levels | A total of 35 trial participants consented to provide serial blood specimens for ionized calcium measurement and pharmacokinetic analysis, per protocol. | Posted | Mean | Standard Deviation | mmoL / liter | In the operating room prior to study drug administration (generally <30 minutes prior to fetal delivery and study drug administration) |
|
|
|
|
| Secondary | Pharmacokinetics of Calcium Chloride - Peak Change in Ionized Calcium From 1 Gram of Calcium Chloride | Generated from a 2-compartment population pharmacokinetic model in NONMEM using serial venous blood gas ionized calcium concentrations. | Participants who participated in the nested pharmacokinetic study and were randomly assigned to the calcium chloride group. | Posted | Mean | 95% Confidence Interval | mmoL / liter | At Tmax (conclusion of the 10-minute intravenous calcium chloride infusion |
|
|
|
|
| Secondary | Pharmacodynamic Effect of Calcium Upon Uterine Tone NRS | Data were not collected. This measure required blood specimens to be obtained at the time of tone scores and this was not done. | Data not collected (unable to obtain blood specimens at the time of tone scores) | Posted | Within 20 minutes of study drug administration |
|
|
| Other Pre-specified | Quantitative Blood Loss, Subgroup Quantitative Blood Loss (QBL, mL), Excluding Cases of Documented Non-atonic Bleeding | Pre-specified subgroup analysis of primary outcome: Because the proposed mechanism of calcium action-improving uterine contractility-was not expected to improve bleeding from causes such as hysterotomy extension or arterial bleeding, the trial was powered for a prespecified subgroup analysis excluding patients with nonatonic blood loss documented in the surgeon's operative report. Documented nonatonic bleeding was defined as presence in the surgeon's operative report narrative of any of the following: hysterotomy extension, hysterotomy types other than low transverse (eg classical, T- or J-shaped), invasive or abnormally adherent placenta, placental abruption, uterine rupture, bleeding from leiomyomas, grade 3 or 4 vaginal lacerations, or cervical lacerations. | Pre=specified subgroup analysis, excluded cases of documented nonatonic bleeding (mostly due to hysterotomy extension, present in 21 participants allocated to calcium and 20 participants allocated to placebo). | Posted | Median | Inter-Quartile Range | milliliters | Calculated at conclusion of operating room case |
|
|
|
|
| 0 |
| 60 |
| 0 |
| 60 |
| 23 |
| 60 |
| EG001 | Saline Placebo | 60mL sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. | 0 | 60 | 0 | 60 | 25 | 60 |
| New or increased vomiting | Gastrointestinal disorders | Vomiting | Systematic Assessment | If patient began vomiting or experienced subjective worsening after initiating study drug infusion. |
|
| Intravenous line pain | Skin and subcutaneous tissue disorders | IV pain | Systematic Assessment | Burning or discomfort at or proximal to the site of the intravenous line |
|
| Flushing | Skin and subcutaneous tissue disorders | Flushing | Systematic Assessment | Patient perception of hot or flushed skin |
|
| Change in heart rate | Cardiac disorders | Heart rate change | Systematic Assessment | Clinically significant changes in heart rate for which the anesthesiologist administered a treatment medication (ie glycopyrrolate, epinephrine, or atropine for bradycardia, beta blockade, phenylephrine, etc for tachycardia) |
|
| Severe range hypertension | Cardiac disorders | Hypertension | Systematic Assessment | Hypertension (>160mmHg systolic or >100mmHg diastolic) resulting in treatment with an intravenous antihypertensive agent |
|
| Abnormal tastes or sensations | Nervous system disorders | Taste | Systematic Assessment | Patient note of any abnormal tastes or subjective abnormal sensations |
|
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| D000091642 | Urogenital Diseases |
| D011644 | Puerperal Disorders |
| D014592 | Uterine Hemorrhage |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D017606 |
| Chlorine Compounds |