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The investigators plan to randomise participants to receive ketamine or placebo control subcutaneously or by 40-minute intravenous infusions and will follow them up for 42 days to assess the incidence of postpartum depression. This feasibility pilot study is designed to explore the adequacy of the study procedures and tolerability of the interventions.
Postpartum depression (PPD)
PPD is one of the most common perinatal medical complications and can have a detrimental effect on both mother and baby. Suicide exceeds hemorrhage and hypertensive disorders as a cause of maternal mortality and maternal psychopathology interferes with the parent-infant relationship. It has been estimated to have a period prevalence of 19.2% in the first 3 postpartum months. The rapid decline in reproductive hormones is thought to contribute to the development of PPD in susceptible women, although the specific pathogenesis is unknown. The American College of Obstetricians and Gynecologists recommend that all women should be routinely screened for depressive symptoms in the perinatal period.
Risk factors for PPD include:
Ketamine's anti-depressant effect
Ketamine, a phencyclidine derivative, is a non-competitive antagonist at the N-methyl-D-aspartic acid (NMDA) receptor that is commonly used as an anesthetic or sedative agent and has proven analgesic effect after a variety of surgeries including CD, where it has also been shown to reduce shivering. It has been demonstrated to have a rapid anti-depressant effect in treatment-resistant depression outside of pregnancy. The most commonly employed intravenous (IV) dose for this purpose is 0.5 mg/kg over 40 minutes, as single or repeated infusions. It has been postulated that prolonged blockade of NMDA receptors causes long-term changes in signal transduction leading to sustained clinical improvement, some investigators have explored longer term infusions such as those used to treat chronic pain. A recent pilot study assessing the feasibility of a 96-hour (~0.5mg/kg/hr) infusion compared with a single 40-minute (0.5 mg/kg) infusion suggested a trend toward greater efficacy in the prolonged infusion but confirmation of a statistically significant result is awaited.
Ketamine and PPD
This promising anti-depressant effect has prompted investigation of ketamine as a preventative measure in patients undergoing CD. There have been 2 studies to date, one which failed to demonstrate any benefit from a bolus dose of 0.25 mg/kg and one which documented a large reduction (1 and 22% in the treatment and control, respectively) in the (6 week) period prevalence of postpartum depression after a 4 mg/kg dose of ketamine over 50 hours (~0.08 mg/kg/hr).
The prolonged IV infusion, was achieved by adding the ketamine to a sufentanil patient-controlled analgesic (PCA) pump with a background infusion. This PCA pump is a standard part of their post-cesarean analgesic regimen. In our institution, it is standard practice to discontinue IV infusions and to remove IV cannulae as early as it is safe to do so. This practice is essential to the attempts to enhance postoperative recovery and aid mother's bonding with their babies and facilitate their early-life care. This reflects patients' expectations and preferences and is in line with other maternity units across North America and Europe.
The natural course of PPD varies and, although it may resolve spontaneously within weeks, approximately 20% of women with PPD still have depression at 12 months and beyond. As many as 13% will still have depressive symptoms at 2 years and 40% will have a relapse. Considering the maternal suffering, disruption to the family, potential impairment of the social, emotional, and cognitive development of the child, and the rare cases of infanticide and suicide caused by PPD, the impact on families and society as a whole is difficult to overemphasize. An intervention that promises such a large reduction in this devastating disease warrants extensive research. In an attempt to achieve the benefit whilst employing methods more acceptable to our patients we have designed a pilot study to assess the feasibility of our study design and collect preliminary tolerability and efficacy data on ketamine administered by two alternative routes: 40-minute IV infusion (i.v.) and subcutaneous (s.c.) injection.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control | Placebo Comparator | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection and 40-minute intravenous infusion of 0.9% sodium chloride. |
|
| Ketamine SC | Experimental | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.5 mg/kg of ketamine and a 40-minute intravenous infusion of 0.9% sodium chloride. |
|
| Ketamine IVI | Experimental | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketamine 50 MG/ML | Drug | Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion). |
|
| Measure | Description | Time Frame |
|---|---|---|
| The Prevalence of Postpartum Depression in the Study Population, as Defined as EPDS Greater Than 10 Out of 30 | Establish a sufficient burden of disease (>10%) in our population to warrant a full RCT | 42 days postpartum |
| Percentage of Eligible Patients Consenting to Participation | Establish a recruitment rate of greater than 50% to confirm the feasibility of conducting an RCT in our population Twenty-five (20.7%) out of 121 women who were approached consented to participation. 2 were withdrawn with 23 completing participation. | Through study completion, approximately 9 months |
| Percentage of Patients With a Complete Dataset | Ensure that the design of assessments and data collection make it possible to achieve a complete dataset in >90% of participants | Through study completion, approximately 9 months |
| Number of Patients in Study Arms Experiencing One or More Severe Side Effects | Ascertain that neither of the chosen routes of administration of ketamine are intolerable to patients, as defined as the incidence of one or more severe side effects experienced by >10% of participants in that study arm. | Through study completion, approximately 9 months |
| Measure | Description | Time Frame |
|---|---|---|
| Dose of Opiate Analgesics Administered | Intraoperative supplementary analgesia in morphine milligram equivalents | Intraoperative phase, approximately 2 hours |
| Dose of Ketorolac Administered (mg) |
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Inclusion criteria:
Exclusion criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University in St. Louis | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36271352 | Derived | Monks DT, Palanisamy A, Jaffer D, Singh PM, Carter E, Lenze S. A randomized feasibility pilot-study of intravenous and subcutaneous administration of ketamine to prevent postpartum depression after planned cesarean delivery under neuraxial anesthesia. BMC Pregnancy Childbirth. 2022 Oct 21;22(1):786. doi: 10.1186/s12884-022-05118-8. |
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2 participants withdrew from the study; only 23 had data to report.
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| ID | Title | Description |
|---|---|---|
| FG000 | Control | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection and 40-minute intravenous infusion of 0.9% sodium chloride. Control: Administration of 0.9% Sodium Chloride (N/S) |
| FG001 | Ketamine SC | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.5 mg/kg of ketamine and a 40-minute intravenous infusion of 0.9% sodium chloride. Ketamine 50 MG/ML: Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion). Control: Administration of 0.9% Sodium Chloride (N/S) |
| FG002 | Ketamine IVI | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine. Ketamine 50 MG/ML: Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion). Control: Administration of 0.9% Sodium Chloride (N/S) |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Control | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection and 40-minute intravenous infusion of 0.9% sodium chloride. Control: Administration of 0.9% Sodium Chloride (N/S) |
| BG001 | Ketamine SC |
| 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 | The Prevalence of Postpartum Depression in the Study Population, as Defined as EPDS Greater Than 10 Out of 30 | Establish a sufficient burden of disease (>10%) in our population to warrant a full RCT | Posted | Count of Participants | Participants | 42 days postpartum |
|
42 days
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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 | Control | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection and 40-minute intravenous infusion of 0.9% sodium chloride. Control: Administration of 0.9% Sodium Chloride (N/S) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. David Monks | Washington University School of Medicine | 314-323-1845 | dmonks@wustl.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 | Jan 24, 2020 | Aug 1, 2022 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 28, 2020 | Aug 1, 2022 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D019052 | Depression, Postpartum |
| ID | Term |
|---|---|
| D011644 | Puerperal Disorders |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D007649 | Ketamine |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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Participants will be randomised to one of three groups (two interventional and one control).
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The ketamine and placebo study injectates (subcutaneous and intravenous) will be prepared, in way that does not allow differentiation, by pharmacy staff who are otherwise uninvolved in the study. Participants will be allocated to groups using a random sequence generator. The patients, investigators and outcome assessors will remain unaware of their group until data collection is complete for all participants.
| Control | Drug | Administration of 0.9% Sodium Chloride (N/S) |
|
Intraoperative supplementary analgesia
| Intraoperative phase, approximately 2 hours |
| Prevalence of Intraoperative Hypotension | Prevalence of participants with intraoperative hypotension of a systolic BP of less than 90 | Intraoperative phase, approximately 2 hours |
| Maximum Intraoperative Pain (NRS) | Reported maximal level of intraoperative pain on the numerical rating scale 0 - 10, where 0 is no pain and 10 is the worst pain imaginable | Intraoperative phase, approximately 2 hours |
| Adverse Effects | Incidence and severity (mild, moderate or severe) of nausea, vomiting, pruritus, dizziness, sedation, shivering, anxiety, euphoria, hallucinations, amnesia, blurred vision, diplopia, nystagmus | Intraoperative and 2 and 6 hours postoperatively |
| Plasma Concentrations of Ketamine | Assays of venous blood samples | At baseline and approximately 20, 40 and 100 minutes postpartum |
| Total Opiate Consumption in Morphine Equivalents | Morphine equivalents | In the first 2 days postpartum |
| Surgical Site Pain: Numerical Rating Scale (NRS 0-10) | Surgical site pain on a numerical rating scale of 0-10, where 0 is no pain and 10 is the worst pain imaginable. | At 2, 6, 24 and 48 hours after delivery and on postpartum days 21 and 42 |
| Edinburgh Postpartum Depression Scale (EPDS) | The EPDS is a validated measure of depressive symptoms in the postpartum period. The scale is scored between 0 - 30, a higher score represents greater depressive symptomatology. We report the study mean of each participant's mean EPDS score for their postpartum assessments | On postpartum days 1, 2, 21 and 42 |
| Apgar Scores | Apgar score (0-10) comprised of an assessment of neonatal color, tone and crying. A higher score indicates healthier color, tone and crying. | At 1 and 5 minutes after delivery |
| Admission to NICU | Incidence of admission | Postpartum day 1 |
| The Number of Participants Achieving Breastfeeding Success | An indication of whether breastfeeding has been successfully established (Yes or No). | Postpartum days 1 and 2 |
| Prevalence of Intraoperative Hypertension | Prevalence of intraoperative hypertension as defined by number of participants with a systolic blood pressure greater than 140 mmHg | Intraoperative phase, approximately 2 hours |
| Prevalence of Intraoperative Bradycardia | Prevalence of intraoperative bradycardia, defined as number of participants with a heart rate of less than 40 bpm | Intraoperative phase, approximately 2 hours |
| Prevalence of Intraoperative Tachycardia | Prevalence of intraoperative tachycardia as defined by the number of participants with a heart rate greater than 110 bpm | Intraoperative phase, approximately 2 hours |
| Postpartum Anxiety | Mean Anxiety in the postpartum. General Anxiety Disorder 7-item Scale (GAD-7), ranges from 0 to 21. Higher scores indicate more severe anxiety. | On day of surgery, and postpartum days 1, 2, 21 and 42 |
Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.5 mg/kg of ketamine and a 40-minute intravenous infusion of 0.9% sodium chloride. Ketamine 50 MG/ML: Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion). Control: Administration of 0.9% Sodium Chloride (N/S) |
| BG002 | Ketamine IVI | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine. Ketamine 50 MG/ML: Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion). Control: Administration of 0.9% Sodium Chloride (N/S) |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| BMI | Mean | Standard Deviation | kg/m^2 |
|
| Gestational age (weeks) | Mean | Standard Deviation | weeks |
|
| American Society of Anesthesiologists' (ASA) physical status classification system | The purpose of the ASA classification system is to assess and communicate a patient's pre-anesthesia medical co-morbidities. The classification system alone does not predict the perioperative risks, but used with other factors (eg, type of surgery, frailty, level of deconditioning), it can be helpful in predicting perioperative risks. Classified as I - IV, with healthier patients being scored as I and sicker patients as IV. | Count of Participants | Participants |
|
| Insurance status | Count of Participants | Participants |
|
| Pre-operative Anxiety, Depression and Psychosocial Stress screening | General Anxiety Disorder 7-item Scale (GAD-7), ranges from 0 to 21. Higher scores indicate more severe anxiety. Edinburgh Postpartum Depression Scale (EPDS) is a set of ten questions assessing mood in the previous seven days. Scored 0-30. Higher scores indicate greater depressive symptomatology. The Antenatal Risk Questionnaire (ANRQ) is a patient-reported psychosocial assessment instrument. Scored 0-23, with higher scores indicating higher psychosocial risk factors. | Mean | Standard Deviation | units on a scale |
|
| Psychiatric history | Count of Participants | Participants |
|
| OG002 | Ketamine IVI | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine. Ketamine 50 MG/ML: Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion). Control: Administration of 0.9% Sodium Chloride (N/S) |
|
|
| Primary | Percentage of Eligible Patients Consenting to Participation | Establish a recruitment rate of greater than 50% to confirm the feasibility of conducting an RCT in our population Twenty-five (20.7%) out of 121 women who were approached consented to participation. 2 were withdrawn with 23 completing participation. | Posted | Count of Participants | Participants | Through study completion, approximately 9 months |
|
|
|
| Primary | Percentage of Patients With a Complete Dataset | Ensure that the design of assessments and data collection make it possible to achieve a complete dataset in >90% of participants | Posted | Count of Participants | Participants | Through study completion, approximately 9 months |
|
|
|
| Primary | Number of Patients in Study Arms Experiencing One or More Severe Side Effects | Ascertain that neither of the chosen routes of administration of ketamine are intolerable to patients, as defined as the incidence of one or more severe side effects experienced by >10% of participants in that study arm. | Posted | Count of Participants | Participants | Through study completion, approximately 9 months |
|
|
|
| Secondary | Dose of Opiate Analgesics Administered | Intraoperative supplementary analgesia in morphine milligram equivalents | Posted | Mean | Standard Deviation | Morphine Milligram Equivalents | Intraoperative phase, approximately 2 hours |
|
|
|
| Secondary | Dose of Ketorolac Administered (mg) | Intraoperative supplementary analgesia | Posted | Mean | Standard Deviation | mg | Intraoperative phase, approximately 2 hours |
|
|
|
| Secondary | Prevalence of Intraoperative Hypotension | Prevalence of participants with intraoperative hypotension of a systolic BP of less than 90 | Posted | Count of Participants | Participants | Intraoperative phase, approximately 2 hours |
|
|
|
| Secondary | Maximum Intraoperative Pain (NRS) | Reported maximal level of intraoperative pain on the numerical rating scale 0 - 10, where 0 is no pain and 10 is the worst pain imaginable | Posted | Mean | Full Range | Rating Score | Intraoperative phase, approximately 2 hours |
|
|
|
| Secondary | Adverse Effects | Incidence and severity (mild, moderate or severe) of nausea, vomiting, pruritus, dizziness, sedation, shivering, anxiety, euphoria, hallucinations, amnesia, blurred vision, diplopia, nystagmus | Posted | Count of Participants | Participants | Intraoperative and 2 and 6 hours postoperatively |
|
|
|
| Secondary | Plasma Concentrations of Ketamine | Assays of venous blood samples | Ketamine assays not performed and therefore no data collected | Posted | At baseline and approximately 20, 40 and 100 minutes postpartum |
|
|
| Secondary | Total Opiate Consumption in Morphine Equivalents | Morphine equivalents | Posted | Mean | Standard Deviation | Morphine Milligram Equivalents | In the first 2 days postpartum |
|
|
|
| Secondary | Surgical Site Pain: Numerical Rating Scale (NRS 0-10) | Surgical site pain on a numerical rating scale of 0-10, where 0 is no pain and 10 is the worst pain imaginable. | Posted | Mean | Full Range | units on a scale | At 2, 6, 24 and 48 hours after delivery and on postpartum days 21 and 42 |
|
|
|
|
| Secondary | Edinburgh Postpartum Depression Scale (EPDS) | The EPDS is a validated measure of depressive symptoms in the postpartum period. The scale is scored between 0 - 30, a higher score represents greater depressive symptomatology. We report the study mean of each participant's mean EPDS score for their postpartum assessments | Posted | Mean | Full Range | units on a scale | On postpartum days 1, 2, 21 and 42 |
|
|
|
|
| Secondary | Apgar Scores | Apgar score (0-10) comprised of an assessment of neonatal color, tone and crying. A higher score indicates healthier color, tone and crying. | Posted | Median | Standard Deviation | score on a scale | At 1 and 5 minutes after delivery |
|
|
|
| Secondary | Admission to NICU | Incidence of admission | Posted | Count of Participants | Participants | Postpartum day 1 |
|
|
|
| Secondary | The Number of Participants Achieving Breastfeeding Success | An indication of whether breastfeeding has been successfully established (Yes or No). | Posted | Count of Participants | Participants | Postpartum days 1 and 2 |
|
|
|
| Secondary | Prevalence of Intraoperative Hypertension | Prevalence of intraoperative hypertension as defined by number of participants with a systolic blood pressure greater than 140 mmHg | Posted | Count of Participants | Participants | Intraoperative phase, approximately 2 hours |
|
|
|
| Secondary | Prevalence of Intraoperative Bradycardia | Prevalence of intraoperative bradycardia, defined as number of participants with a heart rate of less than 40 bpm | Posted | Count of Participants | Participants | Intraoperative phase, approximately 2 hours |
|
|
|
| Secondary | Prevalence of Intraoperative Tachycardia | Prevalence of intraoperative tachycardia as defined by the number of participants with a heart rate greater than 110 bpm | Posted | Count of Participants | Participants | Intraoperative phase, approximately 2 hours |
|
|
|
| Secondary | Postpartum Anxiety | Mean Anxiety in the postpartum. General Anxiety Disorder 7-item Scale (GAD-7), ranges from 0 to 21. Higher scores indicate more severe anxiety. | Posted | Mean | Full Range | units on a scale | On day of surgery, and postpartum days 1, 2, 21 and 42 |
|
|
|
|
| 0 |
| 7 |
| 0 |
| 7 |
| 7 |
| 7 |
| EG001 | Ketamine SC | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.5 mg/kg of ketamine and a 40-minute intravenous infusion of 0.9% sodium chloride. Ketamine 50 MG/ML: Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion). Control: Administration of 0.9% Sodium Chloride (N/S) | 0 | 8 | 0 | 8 | 6 | 8 |
| EG002 | Ketamine IVI | Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine. Ketamine 50 MG/ML: Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion). Control: Administration of 0.9% Sodium Chloride (N/S) | 0 | 8 | 0 | 8 | 6 | 8 |
| Vomiting | General disorders | Non-systematic Assessment |
|
| Shivering | General disorders | Non-systematic Assessment |
|
| Sedation | Surgical and medical procedures | Non-systematic Assessment |
|
| Blurred vision | Eye disorders | Non-systematic Assessment |
|
| Diplopia | Eye disorders | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
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| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| Title | Measurements |
|---|---|
|
| Severe Nausea |
|
| Mild vomiting |
|
| Moderate vomiting |
|
| Severe vomiting |
|
| Mild shivering |
|
| Moderate shivering |
|
| Severe Shivering |
|
| Mild sedation |
|
| Moderate sedation |
|
| Severe sedation |
|
| Mild blurred vision |
|
| Moderate blurred vision |
|
| Severe blurred vision |
|
| Mild diplopia |
|
| Moderate diplopia |
|
| Severe diplopia |
|
| Mild dizziness |
|
| Moderate dizziness |
|
| Severe dizziness |
|
| Mild anxiety |
|
| Moderate anxiety |
|
| Severe anxiety |
|
| Mild pruritus |
|
| Moderate pruritus |
|
| Severe pruritus |
|
| Euphoria |
|
| Amnesia |
|
| Hallucinations |
|
| Nystagmus |
|
|
| 24 hours postoperatively |
|
| 48 hours postoperatively |
|
| 21 days postoperatively |
|
| 42 days postoperatively |
|
|
| Day 21 |
|
| Day 42 |
|
|
| Title | Measurements |
|---|---|
|
|
| Day 21 |
|
| Day 42 |
|