- Email: [email protected]
ICU management of the obstetric patient
Journal Pre-proof ICU management of the obstetric patient Sima Patel, Andrea Estevez, Nicholas Nedeff, Jose Gascon, Ilde Lee PII:
S2210-8440(19)30073-5
DOI:
https://doi.org/10.1016/j.tacc.2020.02.003
Reference:
TACC 1014
To appear in:
Trends in Anaesthesia and Critical Care
Received Date: 15 May 2019 Revised Date:
11 February 2020
Accepted Date: 12 February 2020
Please cite this article as: Patel S, Estevez A, Nedeff N, Gascon J, Lee I, ICU management of the obstetric patient, Trends in Anaesthesia and Critical Care (2020), doi: https://doi.org/10.1016/ j.tacc.2020.02.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.
ICU Management of the Obstetric Patient Sima Patel, MD1; Andrea Estevez, MD2; Nicholas Nedeff, MD3; Jose Gascon, MD2; Ilde Lee, MD4 1 Department of Internal Medicine, Orlando Health Orlando Regional Medical Center, Orlando, Fl 2 Department of Internal Medicine, Kendall Regional Medical Center, Miami, Fl 3 Department of Anesthesiology, Kendall Regional Medical Center, Miami, Fl 4 Department of Critical Care Medicine, Kendall Regional Medical Center, Miami, Fl
Corresponding Author: Dr. Sima Patel, Kendall Regional Medical Center Orlando Health Orlando Regional Medical Center, 52 W Underwood St, Orlando, FL 32806. 11750 Bird Rd, Miami, FL 33175. Phone: 912-220-6952 Email: [email protected]
Disclosures: Author contributors: S. Patel wrote and edited the manuscript, and is the article guarantor. A. Estevez wrote and edited the manuscript. I. Lee, N. Nedeff, and J. Gascon revised the manuscript. Financial disclosure: None to report.
Conflicts of Interest: The authors declare that there is no conflict of interest regarding the publication of this article.
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Abstract Across the United States (U.S.), very few centers exist with an intensive care unit (ICU) solely dedicated to obstetrics (OB) and gynecology (GYN) patients. There are very few facilities around the United States that have an intensive care unit (ICU) solely dedicated to obstetrics (OB) and gynecology (GYN) patients. The management of obstetric patients, who are admitted to a general intensive care unit, can often be accompanied by a fair share of apprehension owing to the intricacy of care. Rather than discussing common obstetric emergencies and their management, we would like to call attention to basic principles that are fundamental in the care of a complicated OB intensive care patient. Understanding the physiologic changes of each trimester and the layers of management is imperative. Having a strong, fundamental knowledge of the plethora of medications and their safety profiles will ensure optimal patient care and dissolve the uncertainty surrounding this unique patient population. Not to mention, grasping a fundamental knowledge of the plethora of medications (and their safety profiles) will improve patient care and dissolve the uncertainty surrounding this unique patient population. What follows is a literature review on sedation, analgesia, airway management, mechanical ventilation and cardiovascular support for critically ill obstetric patients. Introduction Few epidemiological studies observing ICU obstetric admissions are available (1). Occasionally, intensivists find themselves caring for OB patients and struggle to find the optimal manner in which to handle the acuity of the case. Approximately 40,000-120,000 of obstetric patients require ICU care per year in the U.S. (2). Even though the Food and Drug Administration (FDA) letter classification for drug therapy in pregnancy was abandoned in 2015, choosing medications can be daunting on the thought process and cloud the clinical picture. Keeping the new FDA recommendations in mind, it is paramount to recognize the basics of ICU care when it comes to pregnant patients, especially given the scarcity of literature (3, Table 1, Figure 1). Education, team building, and adequate communication are just the beginning of sound critical care. Our interest in this topic stemmed from a pregnant patient who was hospitalized for septic shock. As maternal infection can be asymptomatic or present with flu-like symptoms, it can lead to late diagnoses, spontaneous abortions, stillbirths, preterm labor, and disseminated fetal infection which are devastating outcomes of maternofetal barrier compromisation (4). We would like to stress the importance of learning the adequate management of parous patients in this setting; a topic that may change the outcome of several cases. We found no singular paper or article which summarized the basics of ICU obstetric care, and therefore aimed to give readers a reference that will help with the care of these patients early in the hospital course. This will hopefully allow time to investigate additional research for the specific disease process at hand. As conducting research in pregnant patients is extremely difficult considered taboo, the specifics of the topic remains a mystery and is hardly reviewed during training.
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In the future, retrospective reviews of similar cases may be a method for further data collection in concluding the best recommendations however, will possibly be out of date given the timeconsuming nature of the task. The hurdle to begin observational or retrospective studies is not as high as initiating active or interventional studies in this patient population. Given adequate patient participation, retrospective and observation studies would assist to increase the knowledge base in critical care medicine. It may be worth starting studies on expanding knowledge of benign medication effects and transitioning into medications such as the ones discussed below. However, this task will prove difficult as no concrete information to maternalfetal side effects/ fetal outcomes can be guaranteed.
Methods We conducted a literature search of PUBMED and FDA databases for cases, studies, and drug information reported from 2000-2018 pertaining to ICU care of obstetric/pregnant patients. Our strategy was to review information about cases specifically related to airway management, hemodynamic instability or circulatory shock. We attempted to avoid specific disease processes or conditions which have clear guidelines on care. We also avoided any studies with medications used that were not discussed in this paper or patients with significant comorbidities that could contribute to confounding factors. Additionally, we conducted searches relating to commonly used ICU infusion medications (e.g. sedatives, vasopressors, analgesics, etc.) and assess their safety in pregnancy. We also conducted a manual search of references of selected articles. When using general phrases such as “Pregnancy in the ICU” over 3000 articles were generated; however, were nonspecific to our topic. These included articles on specific medications (those not discussed in this paper), neonatology, viral infections in pregnancy, depression in pregnancy etc. We narrowed our search to the specific pool such has pregnancy, intubation, vasopressors, and sedation. This selection resulted in zero articles. We then began to search each topic individually with key words such as “intubation with pregnancy or obstetrics”, which resulted in 26 articles. We continued our search with the topics discussed below. General search terms included: vasopressors, pregnancy, intubation, obstetrics, specific medications. Discussion A “multi-disciplinary approach” takes on a whole new meaning when caring for the gravid patient in the ICU. The lead intensivist should ensure a combination of experienced nursing staff (both ICU and perinatal), obstetricians, anesthesiologists, pediatricians and pharmacists, as well as any other necessary specialists (1). It is important to understand major physiologic and pharmacokinetic changes that take place during pregnancy, keeping in mind that each trimester may present distinct hurdles. In addition, familiarizing oneself with the FDA Pregnancy and Lactation Labeling Rule (PLLR) will prove essential for adequate patient care (Table 1). It is worth noting that the new PLLR does not consider gestational age in decision making and in the event of an emergency, the mother should receive any medication required to save her life regardless of fetal compromise.
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Our interest in this topic stemmed from a pregnant patient who was hospitalized for septic shock. As maternal infection can be asymptomatic or present with flu-like symptoms, it can lead to late diagnoses, spontaneous abortions, stillbirths, preterm labor, and disseminated fetal infection which are devastating outcomes of maternofetal barrier compromisation (4). We would like to stress the importance of learning the adequate management of parous patients in this setting; a topic that may change the outcome of several cases. Intubation/Airway: Failed intubations have been reported in one in every 550 cases of general anesthesia obstetric cases (5). Intubation failure is reportedly 8-10 times higher in pregnant patients; the higher incidence of intubation failure has been associated with death of 1 per 90 intubations (6). Patients have a shorter time to hypoxia owing to a decreased functional residual capacity which combined with an increase in the basal metabolic rate makes delayed intubation potentially dangerous (1). In addition, physiologic changes such as weight gain, increased vascularity, increased risk of aspiration due to elevated laxity of the lower esophageal sphincter and delayed gastric emptying can make intubation difficult (1, 6, 7). The airway can often be edematous at the level of the vocal cords and above, which can make laryngoscopy more difficult, often requiring the use of a smaller endotracheal tube (ETT) size (7). These anatomical changes can also contribute to worsening the Mallampati score (to grade III or IV), predicting a possible difficult intubation (6). Increased weight gain and breast size may require the use of a short handle laryngoscope. Hence, optimal positioning, preoxygenation and a backup method of intubation in case of difficult intubation is imperative to have. SCCM FCCS recommends starting with size 7 or 6 ETT. (6, 8). Nasal intubation should be avoided in pregnancy due to friable mucosa and capillary dilatation in the upper airway (6). Physiologic changes such as weight gain, increased vascularity, increased risk of aspiration due to elevated laxity of the lower esophageal sphincter, and delayed gastric emptying can make intubation difficult (1, 6, 7). Patients have a shorter time to hypoxia owing to a decreased functional residual capacity which combined with an increase in basal metabolic rate makes delayed intubation potentially dangerous (1). The airway can often be edematous at the level of the vocal cords and above, which can make laryngoscopy more difficult and could require the use of a smaller endotracheal tube (ETT) size (7). SCCM FCCS recommends starting with size 7 or 6 ETT. (6, 8). Nasal intubation should be avoided in pregnancy due to friable mucosa and capillary dilatation in the upper airway (6). These changes can also contribute to worsening the Mallampati score (to grade III or IV) indicating a difficult intubation (6). Increased weight gain and breast size may require the use of a short handle laryngoscope. It is imperative to have optimal positioning, preoxygenation and a backup method of intubation in case of difficult intubation. Succinylcholine crosses the placenta in very small amounts and generally does not cause any neonatal effects; however, non-depolarizing neuromuscular blockers do cross the placenta and may cause significant neonatal neuromuscular blockade (1, 9). Succinylcholine crosses the placenta in very small amounts and generally does not cause any neonatal effects; non-depolarizing neuromuscular blockers have fewer side effects than succinylcholine however, data on placental transfer is limited (1, 9). We recommend having an anesthesiologist present for any anticipated difficult airway. If succinylcholine is contraindicated, then rocuronium at a dose of 1mg/kg can be a suitable replacement for rapid sequence induction. It does cross the placenta
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but not enough to cause neonatal muscle weakness (10). Rocuronium acts in less than 60 seconds and its effects last longer than succinylcholine aiding in more difficult intubations; plus, it has the added benefit of having a reversal agent, sugammadex which, at a dose of 16 mg/kg can reverse the effects of rocuronium for a failed intubation but has not been extensively studied in pregnancy (10, 11). The reversal takes effect in a mean of 2.9 minutes which is faster than the spontaneous reversal effect of succinylcholine (12). Of note, this dose of sugammadex may require multiple vials to achieve a therapeutic effect (11). However, it may not be practical as many facilities do not yet carry the medication and there is little data on the use in pregnant individuals. Mechanical Ventilation: Approximately 0.1-0.2% of pregnancies require mechanical ventilation for respiratory failure (13). Increased minute ventilation during pregnancy results in hypocarbia (and mild respiratory alkalosis) in the first trimester (7). Compared to established acute respiratory distress syndrome (ARDS) guidelines, there is no established evidence for or against using a lung-protective strategy centered around low tidal volumes (≤6 ml/kg predicted body weight) and maintenance of plateau pressures less than 30 cmH2O in pregnancy (1). The optimal level of positive endexpiratory pressure (PEEP) has not been studied in pregnancy and presently, the PEEP protocol in the ARDSNet trial(s) is a reasonable choice for our patients (1). Oxygen consumption increases by 20% or greater at term (8). Obstetric patients develop hypoxia more rapidly (within three minutes of ventilation cessation) when compared to non-obstetric patients, which can theoretically manage up to seven minutes of apnea (8). Correct preoxygenation will require approximately 3 minutes of ventilation with 100% oxygen before anesthesia induction. An oxygen saturation (SpO2) goal of 95% in obstetric patients is sufficient to supply enough oxygen to the developing fetus (14). It is prudent to avoid hypercapnia with lung-protective ventilation as excess CO2 diminishes the gradient across the placenta preventing fetal CO2 from being excreted, causing fetal acidosis (13). Airway pressure release ventilation (APRV) has been studied in small trials but has no specific benefit over other modes of ventilation. Prone ventilation has been shown to provide complete relief of uterine compression of large vessels more than the left lateral position (15). Sedation and Analgesia: The FDA has been studying the possible side effects of sedatives and analgesics on children’s brain development since the first animal study published in 1999 (16-18). The FDA issued a safety warning in 2016 and 2017 that urged providers to be mindful of lengthy (greater than three hours) use of sedatives or analgesics in pregnant patients (16, 17). This warning clearly stated that studies performed preformed in pregnant animals showed that exposure to agents for greater than three hours showed loss of nerve cells in the brain resulting in long tern effects on behavior and learning (16-25). The most common sedatives used in the ICU have been known to cross the placenta to varying degrees depending on the agent and dose (1). Placental transfer is dependent upon many factors but high lipid solubility in pregnancy allows for rapid transfer and may result in particular drugs medications being trapped in the placenta (26). Opioids like fentanyl, morphine, and hydromorphone have been used in pregnancy and can cause respiratory depression as well as withdrawal (1). In April 2018, the FDA issued a draft to include pregnant
5
women in clinical trails, under certain circumstances (27). Some deem it unethical to exclude obstetric patients from trials considering a prospective study with 9546 pregnant patients, determined that 73.4% of patients took medications other than vitamins and supplements (27, 28). Analgesics taken during pregnancy and the first trimester accounted for 23.7% and 15.6% of patients; for which opioids accounted for 3.6% and 1.4% of patients (27, 28). It is crucial to keep the pediatrician informed of any sedatives or analgesics used prior to admission or given during the ICU admission in order to prepare for fetal complications (1). Benzodiazepines such as midazolam and lorazepam, have been used for epilepsy treatment, anxiety management and sedation in the ICU (1, 29). They have been known to cause respiratory depression, floppy baby syndrome, withdrawal symptoms and concern for malformations (1, 30, 31). Propofol was given this designation based on animal studies only (i.e. no well designed controlled studies on pregnant females have been performed) (1, 30). Although it crosses the placenta, there is no evidence that propofol causes propofol infusion syndrome (PRIS) in the fetus (1, 30, 32). Two cases at 9 and 26 weeks gestation showed a progressive non-anion gap acidosis after 10-11 hours of propofol infusions for surgical procedures, but both children were born healthy at full term (33). Furthermore, propofol has been routinely used as an induction agent during general anesthesia for cesarean sections with good outcomes. There have been reports of dexmedetomidine being used in pregnancy more often during the peripartum period without reports of myometrial contraction (1). It is given via a loading dose of 0.5 to 1 µg/kg IV over 10 to 20 minutes, followed by an infusion of 0.2 to 0.7 µg/kg/h (34). Ketamine has been known to cause uterine contraction in early pregnancy, but no effects in late pregnancy (26, 35). High doses of ketamine (10 mg/kg) were not proven to be teratogenic but two recent studies show that exposure of high doses of several hours may be associated with neuroapoptosis in fetal brains of monkeys; more than teratogenicity the concern for neurotoxicity remains high (36). Vasoactive Agents: Blood volume increases starting at week 4 of pregnancy and reaches 30-50% of baseline by 2834 weeks (1, 7, 37). At term, heart rate increases by 15-20 beats per minute; blood pressure decreases in mid-pregnancy (by 5-10 mmHg) but returns to pre-pregnancy range by term (1, 2, 37). Cardiac output (CO) rises by 15-25% by 8 weeks gestation and by term is up to 30-50% of baseline (1, 2). A gravid uterus (> 20 weeks) can compress the inferior vena cava (IVC), decreasing venous return and therefore CO (11). A wedge under the right pelvis or a rightward tilt will displace the uterus away from the IVC, theoretically alleviating the compression (1). The patient should be positioned tilted to the left (ideally at 27°) to relieve aortocaval compression (36, 37, 38). Uteroplacental blood flow is mostly dependent on MAP; vasopressors may be needed to maintain adequate MAP but they have shown to cause placental vasoconstriction (1). Vasopressors chosen in obstetrics are primarily those which are selective alpha 1 agonists (39). Phenylephrine, a purely alpha 1 agonist, has been studied in animals and has been shown to improve fetal acid-base status and increase maternal BP without compromising uterine blood flow (1, 30, 40). Norepinephrine and epinephrine may compromise uterine blood flow at exceedingly high doses (30). Dopamine has been used in a small case series for renal failure prevention in pre-eclampsia and one report documented no adverse effects for mother or infant (41). There is no data on vasopressin use in pregnancy and based on the limited literature, it is preferred to use phenylephrine as the initial agent and then consider norepinephrine or
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epinephrine in refractory cases (30). However, when it comes to septic shock the Surviving Sepsis Guidelines remains the mainstay of therapy (42). Frequent fetal heart monitoring is recommended while the patient is on vasoactive drugs and assessing dynamic parameters of volume assessment (i.e. SVV, SVR, CO, CI, etc) via an arterial line should be highly considered. Resuscitation (i.e. CPR) for pregnant women is overall similar to usual basic life support (BLS) and adult advanced cardiac life support (ACLS). Pregnancy does not change the manner in which vasopressors or defibrillation is used (8, 37, 40). Challenges in these cases are confounded by lack of experience in this population. Less than one in 20,000 pregnant women have been reported to go into cardiac arrest, however there is an extensive variation of arrests from country to country (41, 43, 44). In-hospital BLS and ACLS algorithm should be implemented following cardiac arrest (36, 37). Continuous manual left uterine displacement (Class I AHA recommendation) should be used in patients with the uterus at or above the umbilicus until delivery can be accomplished (36, 41, 37, 43). Owing to body habitus, it may be difficult to oxygenate a patient with conventional face mask ventilation (8). Since hypoxia can occur rapidly, securing an airway is imperative; AHA recommends that interruptions in CPR be limited to 10 seconds however an exception can be made in the event of advanced airway placement. (36, 37, 38). Delivery of fetus improves outcomes of resuscitation of the mother; not only does it improve IVC circulation but it also helps to improve thoracic compliance making compressions more effective (41 43). Keep in mind that resuscitation is would always primarily directed at the mother in an emergency regardless of fetal gestation. Conclusion As there are many constraints in the management of OB patients, it is vastly important to understand the complexities (including basic physiologic changes) involved when caring for this population (7, Table 2, 44). Common disease states are associated with pregnancy and can mandate admission to the ICU: placental abruption, HELLP syndrome, amniotic fluid embolism, eclampsia, etc (12). We are often challenged by complex, multi-layer obstetric cases Often times we are challenged by the specifics, especially when the care becomes complicated (42). Mastery of the core principles of sedatives, analgesics, ventilator management, and vasoactive active agent use in the OB patient aims to ensure timely and safe implementation of therapy (1, 29, 32, 34, 37, 38, Table 3, Table 4). This review is in line with the FCCS/SCCM recommendations as it pertains to mechanical ventilation, vasoactive agents and airway management.
Tables: Table 1: Comparison of Previous Pregnancy Medical Risk Classification to New PLLR Guide (43, 44, 46, 47) Previous Pregnancy Medical Risk Classification
New PLLR Guide
Pregnancy risk letter categories (A, B, C, D, X) assigned.
Pregnancy risk letter categories eliminated.
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Section 8.1 Pregnancy Section 8.2 Labor and Delivery
Combined to create one section: 8.1 Pregnancy ● ● ● ●
Section 8.3 Nursing Mothers
--
Pregnancy Exposure Registry Risk Summary Clinical Considerations Data
Becomes Section 8.2 Lactation ● Risk Summary ● Clinical Considerations ● Data New section added: 8.3 Females and Males of Reproductive Potential* ● Pregnancy ● Testing ● Contraception ● Infertility
PLLR = Pregnancy and Lactation Labeling Rule. *Only included when there are recommendations or requirements for pregnancy testing and/or contraception before,
during, or after drug therapy, and/or there are human and/or animal data suggesting drug-associated effects on fertility and/or preimplantation loss effects.
Table 2: Physiologic Changes of Pregnancy (7) Gastroenterology Gastroesophageal sphincter tone
Decrease
Gastric emptying
Decrease
Pulmonary Minute ventilation
Increase
Tidal Volume
Increase
Respiratory Rate
Increase
Oxygen consumption
Increase
PaO2
Increase
Functional residual capacity
Decrease
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PaCO2
Decrease
Cardiovascular Cardiac Output
Increase
Heart Rate
Increase
Blood pressure
Decrease
Systemic vascular resistance
Decrease
Central venous pressure
Decrease
Pulmonary artery pressure
Decrease
Hematologic Blood volume
Increase
Plasma volume
Increase
Red blood cell volume
Increase
White blood cell volume
Increase
Coagulation factors
Increase
Hematocrit
Decrease
*Abbreviations: PaCO2 = arterial carbon dioxide tension; PaO2 = arterial oxygen tension.
Table 2: Sedatives/Analgesics (29, 32, 33, 48-53, 46-51 28, 31, 45-50) No Name 1
FDA Information
Dexmedetomidine 8.1: No studies in pregnant women to inform drug associated risks
Key Points -
Animal studies: No teratogenic effects were observed in a reproductive toxicology study conducted with dexmedetomidine dosed throughout organogenesis in rats with subcutaneous administration at doses approximately equal to the
-
Has anxiolytic, sedative, hypnotic, and analgesic properties Limited impact on the respiratory system Can reduce heart rate and blood pressure Atipamezole rapidly reversal agent but not routinely readily available
9
maximum recommended human dose 8.2: No information on presence in human milk, effect on breastfed infant, or on milk production Clinical consideration: A lactating woman may consider interrupting breastfeeding, pumping and discarding breast milk for 10 hours after receiving dexmedetomidine to minimize potential drug exposure infant. 8.3: No direct human information on male and female fertility 2
Propofol
8.1: There are no adequate and well-controlled studies in pregnant women. Animal Studies: Decreased pup survival with increased maternal mortality was observed with IV administration of propofol to pregnant rats either prior to mating and during early gestation or during late gestation and early lactation at exposures less than the human induction dose of 2.5 mg/kg
-
-
Produces rapid, profound sedation 1.5 to 2.5 mg/kg IV induces unconsciousness within 30 seconds 25 to 100 µg/kg/min achieves conscious sedation Recovery occurs within minutes Can cause decrease in systemic blood pressure In animal studies has not been shown to have teratogenic effects
Propofol not recommended for obstetrics, including cesarean sections. Propofol crosses the placenta. 8.2: Propofol has been reported to be excreted in human milk and the effects of oral absorption of small amounts are unknown. 8.3: No direct human information on male and female fertility
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3
Fentanyl
8.1: Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates.
-
Animal Data: There was no evidence of teratogenicity reported. 8.2: Fentanyl is present in breast milk. There is insufficient information to determine the effects of fentanyl on the breastfed infant and effects of fentanyl on milk production.
-
Clinical Consideration: Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic or breast feeding is terminated.
Compared to morphine, fentanyl has a more rapid onset and 100 fold greater potency. 1-2 µg/kg causes a peak effect within 5 minutes and continues on for roughly 30 minutes Crosses placenta, if > 1ucg/kg, with reported incidences of respiratory depression Naloxone titrated in 0.04 mg IV increments every 2-3 minutes can reverse pruritus, nausea, & respiratory depression but may precipitate withdrawal symptoms.
8.3: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. Unknown whether the effects on fertility are reversible. 4
Ketamine
8.1: There are no adequate and well-controlled studies of ketamine in pregnant women. Animal Studies: Studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain
-
-
-
Increases heart rate, arterial blood pressure, and cardiac output (along with myocardial oxygen demand); not recommended in women with significant hypertension. Crosses the placenta; limited human data 30 seconds time of onset; 14.5 mg/kg for anesthesia induction. 0.2-0.75 mg/kg for procedural anesthesia.
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of the offspring when used for longer than 3 hours
-
8.2: No documented data in breast-feeding mothers
Subanesthetic doses at 0.2 to 0.5 mg/kg IV occurs within 1 minute of administration and lasts 20 - 60 minutes
8.3: Adequate studies to evaluate the impact of ketamine on male or female fertility have not been conducted. 5
Midazolam
8.1: The use of injectable midazolam in obstetrics has not been evaluated in clinical studies. Midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression. 8.2: Midazolam is excreted in human milk. Maximum neonatal exposure is estimated at only 3% of maternal dose. 8.3: No human data information available on fertility. Animal studies: A reproduction study in male and female rats did not show any impairment of fertility at dosages up to 10 times the human IV dose of 0.35 mg/kg.
Decreases analgesic requirements and diminishes agitation without cardiovascular depression Crosses the placenta (less than diazepam), enters fetal circulation, and may contribute to neonatal depression; including mild sedation, hypotonia, reluctance to suck, apneic spells, cyanosis, impaired metabolic responses to stress, “floppy infant” syndrome, and marked neonatal withdrawal that can persist for hours to months after birth. Premedication prior to Csection may cause maternal amnesia
Table 3: Vasopressors (54-58, 52-56 51-55) No Name
FDA Information
Key Points
1
8.1: Human reproduction studies have not been conducted with norepinephrine.
-
Norepinephrine
8.2: Unknown if this drug is excreted in human milk.
-
May reduce uteroplacental blood flow High IV doses may decrease milk production and inhibit release of oxytocin
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8.3: No human data information available on fertility.
2
Epinephrine
8.1: Epinephrine crosses the placenta. Potential risk to the fetus include fetal anoxia, spontaneous abortion, or both. Epinephrine usually inhibits spontaneous or oxytocin induced contractions of the pregnant human uterus and may delay the second stage of labor.
-
-
May cause fetal tachycardia May result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia. Avoid epinephrine during the second stage of labor.
Animal Studies: Epinephrine is teratogenic in rabbits, mice, and hamsters dosed during organogenesis. 8.2: Unknown whether epinephrine is excreted in human milk. 8.3: No human data information available on fertility. 3
Vasopressin
8.1: No adequate or wellcontrolled studies of vasopressin in pregnant women. May produce tonic uterine contractions that could threaten the continuation of pregnancy.
-
No data of use during pregnancy
8.2: Unknown whether vasopressin is excreted in human milk. Oral absorption by a nursing infant is unlikely because vasopressin is rapidly destroyed in the gastrointestinal tract. Advise a lactating woman to pump and discard breast milk for 1.5 hours after receiving vasopressin to minimize
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exposure to infant. 8.3: No human data information available on fertility.
4
Phenylephrine
8.1: Unknown if phenylephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenylephrine does not appear to cause a decrease in placental perfusion sufficient to alter either the neonate Apgar scores or blood-gas status
-
Ideal for continuous infusion Will improve maternal BP without compromising uterine blood flow
-
May reduce uteroplacental blood flow Only used in a small group of cases for renal failure prevention in pre-eclampsia
8.2: Unknown if this drug is excreted in human milk. 8.3: No human data information available on fertility. 5
Dopamine
8.1: There are no adequate and well-controlled studies in pregnant women, and it is unknown if dopamine crosses the placenta.
-
8.2: Unknown if dopamine is excreted in human milk. 8.3: No human data information available on fertility. Note: It is prudent to adhere to the surviving sepsis guidelines in cases of septic shock. Table 4: Topic Summary
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Topic Airway Management/Intubation
Study Design Multi-center RCT
Article, Authors Lee C, Jahr JS et al
Conclusion Sugammadex can be used as a reversal agent for non-depolarizing neuromuscular blocking agents
Mechanical Ventilation
Case series
Lapinsky SE, et al.
Ventilatory approach was similar to nonpregnant patients; mild hypercapnia is tolerated in pregnancy
Sedation/Analgesia
Case reports
Hilton G, et al
Hemodynamics/Vasoact ive agents
Cross-sectional study
Nakai Y, et al.
Prolonged propofol infusion may be associated with a reversible metabolic acidosis; Maternal prone position can provide complete relief of uterine compression of the large maternal vessels
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Figures: Figure 1: The Food and Drug Administration of the Pregnancy and Lactation Labeling Rule (PLLR)
Resources: 1. Gaffney A. Critical care in pregnancy-is it different? Semin Perinatol. 2014;38:329–40. 2. Obstetrics & Gynecology: October 2016 - Volume 128 - Issue 4 - p e147–e154. doi: 10.1097/AOG.0000000000001710 3. Food and Drug Administration. Pregnancy and Lactation Labeling (Drugs) Final Rule.Fed Regist. 2014. Available at: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ ucm093307.htm. 4. Lamond NM, Freitag NE. Vertical Transmission of Listeria monocytogenes: Probing the Balance between Protection from Pathogens and Fetal Tolerance. Pathogens. 2018;7(2):52. Published 2018 May 25. doi:10.3390/pathogens7020052 5. D'Angelo R., Smiley R. M., Riley E. T., Segal S. Serious complications related to obstetric anesthesia: the serious complication repository project of the society for obstetric Anesthesia and Perinatology. Anesthesiology. 2014;120(6):1505–1512. doi: 10.1097/aln.0000000000000253. 6. Baldisseri MR, Plante LA. Fundamental Critical Care Support: Obstretrics. Mount Prospect, IL: Society of Critical Care Medicine; 2017 7. Bajwa SJS, Bajwa SK. Anaesthetic challenges and management during pregnancy: Strategies revisited. Anesthesia, Essays and Researches. 2013;7(2):160-167. doi:10.4103/0259-1162.118945. 8. Varon AJ, Smith CE. Essentials of Trauma Anesthesia. Cambridge, United Kingdom: Cambridge University Press; 2012: 288-298. 9. Dongare PA, Nataraj MS. Anaesthetic management of obstetric emergencies. Indian J Anaesth. 2018;62(9):704–709. doi:10.4103/ija.IJA_590_18
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10. Mark Rollins, Jennifer Lucero; Overview of anesthetic considerations for Cesarean delivery, British Medical Bulletin, Volume 101, Issue 1, 1 March 2012, Pages 105–125. https://doi.org/10.1093/bmb/ldr050 11. Chaggar RS, Campbell JP (2017) The future of general anaesthesia in obstetrics. BJA Educ 17(3):83–79. doi: 10.1093/bjaed/mkw046 12. Lee C, Jahr JS, Candiotti KA, Warriner B, Zornow MH, Naguib M. Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine. Anesthesiology 2009; 110:1020-5. doi: 10.1097/ALN.0b013e31819dabb0. 13. Lapinsky SE, Rojas-Suarez JA, Crozier TM, Vasquez DN, Barrett N, Austin K. Mechanical ventilation in critically-ill pregnant women a case series. Int J Obstet Anesth. 2015;24(4):323–328. doi: 10.1016/j.ijoa.2015.06.009. 14. Cole DE, Taylor TL, Mccullough DM, Shoff CT, Derdak S. Acute respiratory distress syndrome in pregnancy. Crit Care Med. 2005; 33:S269-S278. 15. Nakai Y, Mine M, Nishio J, Maeda T, Imanaka M, Ogita S. Effects of maternal prone position on the umbilical arterial flow. Acta Obstet Gynecol Scand. 1998;77:967–969. doi: 10.1080/j.1600-0412.1998.771003. 16. Food and Drug Administration. FDA Drug Safety Communication. Available at: 2016. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communicationfda-review-results-new-warnings-about-using-general-anesthetics-and. Accessed May 7, 2019. 17. Food and Drug Administration. FDA Drug Safety Communication. Available at: 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communicationfda-approves-label-changes-use-general-anesthetic-and-sedation-drugs. Accessed May 7, 2019. 18. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-4. 19. Brambrink AM, Back SA, Riddle A, et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72(4):525–535. doi:10.1002/ana.23652. 20. Brambrink AM, Evers AS, Avidan MS, et al. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology. 2012;116(2):372–384. doi:10.1097/ALN.0b013e318242b2cd. 21. Briner A, Nikonenko I, De Roo M, Dayer A, Muller D, Vutskits L. Developmental Stagedependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology 2011;115:282-93. doi: 10.1097/ALN.0b013e318221fbbd. 22. Creeley CE, Dikranian KT, Dissen GA, Back SA, Olney JW, Brambrink AM. Isofluraneinduced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. Anesthesiology. 2014;120(3):626–638. doi:10.1097/ALN.0000000000000037. 23. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82.
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24. Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 2011;33:220-30. doi: 10.1016/j.ntt.2011.01.001. 25. Scallet AC, Schmued LC, Slikker W Jr, Grunberg N, Faustino PJ, Davis H, et al. Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol Sci 2004;81:364-70. 26. Upadya M, Saneesh PJ. Anaesthesia for non-obstetric surgery during pregnancy. Indian J Anaesth. 2016;60(4):234–241. doi:10.4103/0019-5049.179445. 27. Rubin, R. Addressing barriers to inclusion of pregnant women in clinical trials. 2018; JAMA, 320,742– 744. doi: 10.1001/jama.2018.9989. 28. Haas DM, Marsh DJ, Dang DT, et al. Prescription and Other Medication Use in Pregnancy. Obstet Gynecol. 2018;131(5):789–798. doi:10.1097/AOG.0000000000002579 29. Buhimschi CS, Weiner CP. Medications in pregnancy and lactation: part 1. Teratology Obstetrics and Gynecology. 2009;113:166–188. doi: 10.1097/AOG.0b013e31818d6788. 30. Hockman RH, Kelsey J. Pregnancy in the ICU - Drug Implications. SCCM.org. http://myicucare.net/Communications/Critical-Connections/Archives/Pages/Pregnancyin-the-ICU---Drug-Implications.aspx. Published August 4, 2010. 31. Freyer AM. Drugs in Pregnancy and Lactation 8th Edition: A Reference Guide to Fetal and Neonatal Risk. Obstet Med. 2009;2(2):89. doi:10.1258/om.2009.090002 32. Hemphill S, McMenamin L, Bellamy MC, Hopkins PM. Propofol infusion syndrome: a structured literature review and analysis of published case reports. Br J Anaesth. 2019;122(4):448–459. doi:10.1016/j.bja.2018.12.025 33. Hilton G, et al. Prolonged propofol infusions in pregnant neurosurgical patients. J Neurosurg Anesthesiol. 2007; 19:67-68. doi: 10.1097/ANA.0b013e31802b31c8 34. Toledano RD, Kodali BS, Camann WR. Anesthesia drugs in the obstetric and gynecologic practice. Rev Obstet Gynecol. 2009;2(2):93-100. 35. Oats JN, Vasey DP, Waldron BA. Effects of ketamine on the pregnant uterus. Br J Anaesth. 1979;51:1163–6. 36. Pinyavat T, Warner DO, Flick RP, et al. Summary of the update session on clinical neurotoxicity studies. J Neurosurg Anesthesiol 2016;28:356-360 37. Jeejeebhoy FM, Zelop CM, Lipman S, et al; for American Heart Association Emergency Cardiovascular Care Committee, Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Cardiovascular Diseases in the Young, and Council on Clinical Cardiology. Cardiac arrest in pregnancy: a scientific statement from the American Heart Association. Circulation. 2015;132(18):1747–1773. 38. Campbell TA, Sanson TG. Cardiac arrest and pregnancy. J Emerg Trauma Shock. 2009;2(1):34–42. doi:10.4103/0974-2700.43586. 39. Nag DS, Samaddar DP, Chatterjee A, Kumar H, Dembla A. Vasopressors in obstetric anesthesia: A current perspective. World J Clin Cases. 2015;3(1):58–64. doi:10.12998/wjcc.v3.i1.58. 40. Practice Guidelines for Obstetric Anesthesia: An Updated Report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia and the Society for Obstetric Anesthesia and Perinatology. Anesthesiology 2016;124(2):270-300. doi: 10.1097/ALN.0000000000000935.
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41. Kirshon B, et al. Effects of low-dose dopamine therapy in the oliguric patient with preeclampsia. Am J Obstet Gynecol. 1988; 159:604-607. 42. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304–377. 43. Truhlář A, Deakin CD, Soar J, Khalifa GEA, Alfonzo A, Bierens JJLM, et al. European resuscitation council guidelines for resuscitation 2015. Resuscitation. 2015;95:148–201. doi: 10.1016/j.resuscitation.2015.07.017. 44. Lipman S, Cohen S, Einav S, et al. The Society for Obstetric Anesthesia and Perinatology consensus statement on the management of cardiac arrest in pregnancy. Anesth Analg. 2014;118(5):1003–1016. doi: doi: 10.1213/ANE.0000000000000171. 45. Soubra SH, Guntupalli KK. Critical illness in pregnancy: an overview. Crit Care Med 2005;33(10 Suppl):S248–55. doi:10.1097/01.CCM.0000183159.31378.6A. 46. Pernia S, DeMaagd G. The New Pregnancy and Lactation Labeling Rule. P T. 2016;41(11):713–715. 47. Food and Drug Administration. Content and format of labeling for human prescription drug and biological products: requirements for pregnancy and lactation labeling. Fed Regist. 2014;79(233):72064–72103. Available at: www.gpo.gov/fdsys/pkg/FR-2014-1204/pdf/2014-28241.pdf. 48. Food and Drug Administration. Center for Drug Evaluation and Research: Dexmedetomidine. 2015. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206628Orig1s000OtherR.pdf. Accessed April 16, 2019. 49. Food and Drug Administration. Center for Drug Evaluation and Research: Fentanyl. 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016619s038lbl.pdf. Accessed April 16, 2019. 50. Food and Drug Administration. Center for Drug Evaluation and Research: Propofol. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019627s066lbl.pdf. Accessed April 16, 2019. 51. Food and Drug Administration. Center for Drug Evaluation and Research: Ketamine. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016812s040lbl.pdf. Accessed April 16, 2019. 52. Food and Drug Administration. Center for Drug Evaluation and Research: Midazolam. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208878Orig1s000lbl.pdf. Accessed April 16, 2019. 53. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):521–546. doi:10.1097/AAP.0000000000000808
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54. Food and Drug Administration. Center for Drug Evaluation and Research: Phenylephrine. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203826s000lbl.pdf 55. Food and Drug Administration. Center for Drug Evaluation and Research: Dopamine. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019615s024lbl.pdf. Accessed April 16, 2019. 56. Food and Drug Administration. Center for Drug Evaluation and Research: Levophed. 2007. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/007513Orig1s024lbl.pdf. Accessed April 16, 2019. 57. Food and Drug Administration. Center for Drug Evaluation and Research: Epinephrine. Available at: 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205029s004lbl.pdf. Accessed April 16, 2019. 58. Food and Drug Administration. Center for Drug Evaluation and Research: Vasopressin. Available at: 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/204485Orig1s004.pdf. Accessed April 16, 2019.
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Highlights: • • • •
A multidisciplinary approach is optimal for the long term care of a parous ICU patient Therapy, in an emergency, should be guided primarily toward the mother even though the fetus is commonly thought about. The new pregnancy and lactation labeling rule should be familiarized as the category labeling has been abandoned by the Food and Drug Administration. Open communication with your neonatologist/pediatrician is necessary when using sedatives, analgesics, and vasoactive agents for long periods of time.
Conflicts of Interest: The authors declare that there is no conflict of interest regarding the publication of this article.
S2210-8440(19)30073-5
DOI:
https://doi.org/10.1016/j.tacc.2020.02.003
Reference:
TACC 1014
To appear in:
Trends in Anaesthesia and Critical Care
Received Date: 15 May 2019 Revised Date:
11 February 2020
Accepted Date: 12 February 2020
Please cite this article as: Patel S, Estevez A, Nedeff N, Gascon J, Lee I, ICU management of the obstetric patient, Trends in Anaesthesia and Critical Care (2020), doi: https://doi.org/10.1016/ j.tacc.2020.02.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.
ICU Management of the Obstetric Patient Sima Patel, MD1; Andrea Estevez, MD2; Nicholas Nedeff, MD3; Jose Gascon, MD2; Ilde Lee, MD4 1 Department of Internal Medicine, Orlando Health Orlando Regional Medical Center, Orlando, Fl 2 Department of Internal Medicine, Kendall Regional Medical Center, Miami, Fl 3 Department of Anesthesiology, Kendall Regional Medical Center, Miami, Fl 4 Department of Critical Care Medicine, Kendall Regional Medical Center, Miami, Fl
Corresponding Author: Dr. Sima Patel, Kendall Regional Medical Center Orlando Health Orlando Regional Medical Center, 52 W Underwood St, Orlando, FL 32806. 11750 Bird Rd, Miami, FL 33175. Phone: 912-220-6952 Email: [email protected]
Disclosures: Author contributors: S. Patel wrote and edited the manuscript, and is the article guarantor. A. Estevez wrote and edited the manuscript. I. Lee, N. Nedeff, and J. Gascon revised the manuscript. Financial disclosure: None to report.
Conflicts of Interest: The authors declare that there is no conflict of interest regarding the publication of this article.
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Abstract Across the United States (U.S.), very few centers exist with an intensive care unit (ICU) solely dedicated to obstetrics (OB) and gynecology (GYN) patients. There are very few facilities around the United States that have an intensive care unit (ICU) solely dedicated to obstetrics (OB) and gynecology (GYN) patients. The management of obstetric patients, who are admitted to a general intensive care unit, can often be accompanied by a fair share of apprehension owing to the intricacy of care. Rather than discussing common obstetric emergencies and their management, we would like to call attention to basic principles that are fundamental in the care of a complicated OB intensive care patient. Understanding the physiologic changes of each trimester and the layers of management is imperative. Having a strong, fundamental knowledge of the plethora of medications and their safety profiles will ensure optimal patient care and dissolve the uncertainty surrounding this unique patient population. Not to mention, grasping a fundamental knowledge of the plethora of medications (and their safety profiles) will improve patient care and dissolve the uncertainty surrounding this unique patient population. What follows is a literature review on sedation, analgesia, airway management, mechanical ventilation and cardiovascular support for critically ill obstetric patients. Introduction Few epidemiological studies observing ICU obstetric admissions are available (1). Occasionally, intensivists find themselves caring for OB patients and struggle to find the optimal manner in which to handle the acuity of the case. Approximately 40,000-120,000 of obstetric patients require ICU care per year in the U.S. (2). Even though the Food and Drug Administration (FDA) letter classification for drug therapy in pregnancy was abandoned in 2015, choosing medications can be daunting on the thought process and cloud the clinical picture. Keeping the new FDA recommendations in mind, it is paramount to recognize the basics of ICU care when it comes to pregnant patients, especially given the scarcity of literature (3, Table 1, Figure 1). Education, team building, and adequate communication are just the beginning of sound critical care. Our interest in this topic stemmed from a pregnant patient who was hospitalized for septic shock. As maternal infection can be asymptomatic or present with flu-like symptoms, it can lead to late diagnoses, spontaneous abortions, stillbirths, preterm labor, and disseminated fetal infection which are devastating outcomes of maternofetal barrier compromisation (4). We would like to stress the importance of learning the adequate management of parous patients in this setting; a topic that may change the outcome of several cases. We found no singular paper or article which summarized the basics of ICU obstetric care, and therefore aimed to give readers a reference that will help with the care of these patients early in the hospital course. This will hopefully allow time to investigate additional research for the specific disease process at hand. As conducting research in pregnant patients is extremely difficult considered taboo, the specifics of the topic remains a mystery and is hardly reviewed during training.
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In the future, retrospective reviews of similar cases may be a method for further data collection in concluding the best recommendations however, will possibly be out of date given the timeconsuming nature of the task. The hurdle to begin observational or retrospective studies is not as high as initiating active or interventional studies in this patient population. Given adequate patient participation, retrospective and observation studies would assist to increase the knowledge base in critical care medicine. It may be worth starting studies on expanding knowledge of benign medication effects and transitioning into medications such as the ones discussed below. However, this task will prove difficult as no concrete information to maternalfetal side effects/ fetal outcomes can be guaranteed.
Methods We conducted a literature search of PUBMED and FDA databases for cases, studies, and drug information reported from 2000-2018 pertaining to ICU care of obstetric/pregnant patients. Our strategy was to review information about cases specifically related to airway management, hemodynamic instability or circulatory shock. We attempted to avoid specific disease processes or conditions which have clear guidelines on care. We also avoided any studies with medications used that were not discussed in this paper or patients with significant comorbidities that could contribute to confounding factors. Additionally, we conducted searches relating to commonly used ICU infusion medications (e.g. sedatives, vasopressors, analgesics, etc.) and assess their safety in pregnancy. We also conducted a manual search of references of selected articles. When using general phrases such as “Pregnancy in the ICU” over 3000 articles were generated; however, were nonspecific to our topic. These included articles on specific medications (those not discussed in this paper), neonatology, viral infections in pregnancy, depression in pregnancy etc. We narrowed our search to the specific pool such has pregnancy, intubation, vasopressors, and sedation. This selection resulted in zero articles. We then began to search each topic individually with key words such as “intubation with pregnancy or obstetrics”, which resulted in 26 articles. We continued our search with the topics discussed below. General search terms included: vasopressors, pregnancy, intubation, obstetrics, specific medications. Discussion A “multi-disciplinary approach” takes on a whole new meaning when caring for the gravid patient in the ICU. The lead intensivist should ensure a combination of experienced nursing staff (both ICU and perinatal), obstetricians, anesthesiologists, pediatricians and pharmacists, as well as any other necessary specialists (1). It is important to understand major physiologic and pharmacokinetic changes that take place during pregnancy, keeping in mind that each trimester may present distinct hurdles. In addition, familiarizing oneself with the FDA Pregnancy and Lactation Labeling Rule (PLLR) will prove essential for adequate patient care (Table 1). It is worth noting that the new PLLR does not consider gestational age in decision making and in the event of an emergency, the mother should receive any medication required to save her life regardless of fetal compromise.
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Our interest in this topic stemmed from a pregnant patient who was hospitalized for septic shock. As maternal infection can be asymptomatic or present with flu-like symptoms, it can lead to late diagnoses, spontaneous abortions, stillbirths, preterm labor, and disseminated fetal infection which are devastating outcomes of maternofetal barrier compromisation (4). We would like to stress the importance of learning the adequate management of parous patients in this setting; a topic that may change the outcome of several cases. Intubation/Airway: Failed intubations have been reported in one in every 550 cases of general anesthesia obstetric cases (5). Intubation failure is reportedly 8-10 times higher in pregnant patients; the higher incidence of intubation failure has been associated with death of 1 per 90 intubations (6). Patients have a shorter time to hypoxia owing to a decreased functional residual capacity which combined with an increase in the basal metabolic rate makes delayed intubation potentially dangerous (1). In addition, physiologic changes such as weight gain, increased vascularity, increased risk of aspiration due to elevated laxity of the lower esophageal sphincter and delayed gastric emptying can make intubation difficult (1, 6, 7). The airway can often be edematous at the level of the vocal cords and above, which can make laryngoscopy more difficult, often requiring the use of a smaller endotracheal tube (ETT) size (7). These anatomical changes can also contribute to worsening the Mallampati score (to grade III or IV), predicting a possible difficult intubation (6). Increased weight gain and breast size may require the use of a short handle laryngoscope. Hence, optimal positioning, preoxygenation and a backup method of intubation in case of difficult intubation is imperative to have. SCCM FCCS recommends starting with size 7 or 6 ETT. (6, 8). Nasal intubation should be avoided in pregnancy due to friable mucosa and capillary dilatation in the upper airway (6). Physiologic changes such as weight gain, increased vascularity, increased risk of aspiration due to elevated laxity of the lower esophageal sphincter, and delayed gastric emptying can make intubation difficult (1, 6, 7). Patients have a shorter time to hypoxia owing to a decreased functional residual capacity which combined with an increase in basal metabolic rate makes delayed intubation potentially dangerous (1). The airway can often be edematous at the level of the vocal cords and above, which can make laryngoscopy more difficult and could require the use of a smaller endotracheal tube (ETT) size (7). SCCM FCCS recommends starting with size 7 or 6 ETT. (6, 8). Nasal intubation should be avoided in pregnancy due to friable mucosa and capillary dilatation in the upper airway (6). These changes can also contribute to worsening the Mallampati score (to grade III or IV) indicating a difficult intubation (6). Increased weight gain and breast size may require the use of a short handle laryngoscope. It is imperative to have optimal positioning, preoxygenation and a backup method of intubation in case of difficult intubation. Succinylcholine crosses the placenta in very small amounts and generally does not cause any neonatal effects; however, non-depolarizing neuromuscular blockers do cross the placenta and may cause significant neonatal neuromuscular blockade (1, 9). Succinylcholine crosses the placenta in very small amounts and generally does not cause any neonatal effects; non-depolarizing neuromuscular blockers have fewer side effects than succinylcholine however, data on placental transfer is limited (1, 9). We recommend having an anesthesiologist present for any anticipated difficult airway. If succinylcholine is contraindicated, then rocuronium at a dose of 1mg/kg can be a suitable replacement for rapid sequence induction. It does cross the placenta
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but not enough to cause neonatal muscle weakness (10). Rocuronium acts in less than 60 seconds and its effects last longer than succinylcholine aiding in more difficult intubations; plus, it has the added benefit of having a reversal agent, sugammadex which, at a dose of 16 mg/kg can reverse the effects of rocuronium for a failed intubation but has not been extensively studied in pregnancy (10, 11). The reversal takes effect in a mean of 2.9 minutes which is faster than the spontaneous reversal effect of succinylcholine (12). Of note, this dose of sugammadex may require multiple vials to achieve a therapeutic effect (11). However, it may not be practical as many facilities do not yet carry the medication and there is little data on the use in pregnant individuals. Mechanical Ventilation: Approximately 0.1-0.2% of pregnancies require mechanical ventilation for respiratory failure (13). Increased minute ventilation during pregnancy results in hypocarbia (and mild respiratory alkalosis) in the first trimester (7). Compared to established acute respiratory distress syndrome (ARDS) guidelines, there is no established evidence for or against using a lung-protective strategy centered around low tidal volumes (≤6 ml/kg predicted body weight) and maintenance of plateau pressures less than 30 cmH2O in pregnancy (1). The optimal level of positive endexpiratory pressure (PEEP) has not been studied in pregnancy and presently, the PEEP protocol in the ARDSNet trial(s) is a reasonable choice for our patients (1). Oxygen consumption increases by 20% or greater at term (8). Obstetric patients develop hypoxia more rapidly (within three minutes of ventilation cessation) when compared to non-obstetric patients, which can theoretically manage up to seven minutes of apnea (8). Correct preoxygenation will require approximately 3 minutes of ventilation with 100% oxygen before anesthesia induction. An oxygen saturation (SpO2) goal of 95% in obstetric patients is sufficient to supply enough oxygen to the developing fetus (14). It is prudent to avoid hypercapnia with lung-protective ventilation as excess CO2 diminishes the gradient across the placenta preventing fetal CO2 from being excreted, causing fetal acidosis (13). Airway pressure release ventilation (APRV) has been studied in small trials but has no specific benefit over other modes of ventilation. Prone ventilation has been shown to provide complete relief of uterine compression of large vessels more than the left lateral position (15). Sedation and Analgesia: The FDA has been studying the possible side effects of sedatives and analgesics on children’s brain development since the first animal study published in 1999 (16-18). The FDA issued a safety warning in 2016 and 2017 that urged providers to be mindful of lengthy (greater than three hours) use of sedatives or analgesics in pregnant patients (16, 17). This warning clearly stated that studies performed preformed in pregnant animals showed that exposure to agents for greater than three hours showed loss of nerve cells in the brain resulting in long tern effects on behavior and learning (16-25). The most common sedatives used in the ICU have been known to cross the placenta to varying degrees depending on the agent and dose (1). Placental transfer is dependent upon many factors but high lipid solubility in pregnancy allows for rapid transfer and may result in particular drugs medications being trapped in the placenta (26). Opioids like fentanyl, morphine, and hydromorphone have been used in pregnancy and can cause respiratory depression as well as withdrawal (1). In April 2018, the FDA issued a draft to include pregnant
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women in clinical trails, under certain circumstances (27). Some deem it unethical to exclude obstetric patients from trials considering a prospective study with 9546 pregnant patients, determined that 73.4% of patients took medications other than vitamins and supplements (27, 28). Analgesics taken during pregnancy and the first trimester accounted for 23.7% and 15.6% of patients; for which opioids accounted for 3.6% and 1.4% of patients (27, 28). It is crucial to keep the pediatrician informed of any sedatives or analgesics used prior to admission or given during the ICU admission in order to prepare for fetal complications (1). Benzodiazepines such as midazolam and lorazepam, have been used for epilepsy treatment, anxiety management and sedation in the ICU (1, 29). They have been known to cause respiratory depression, floppy baby syndrome, withdrawal symptoms and concern for malformations (1, 30, 31). Propofol was given this designation based on animal studies only (i.e. no well designed controlled studies on pregnant females have been performed) (1, 30). Although it crosses the placenta, there is no evidence that propofol causes propofol infusion syndrome (PRIS) in the fetus (1, 30, 32). Two cases at 9 and 26 weeks gestation showed a progressive non-anion gap acidosis after 10-11 hours of propofol infusions for surgical procedures, but both children were born healthy at full term (33). Furthermore, propofol has been routinely used as an induction agent during general anesthesia for cesarean sections with good outcomes. There have been reports of dexmedetomidine being used in pregnancy more often during the peripartum period without reports of myometrial contraction (1). It is given via a loading dose of 0.5 to 1 µg/kg IV over 10 to 20 minutes, followed by an infusion of 0.2 to 0.7 µg/kg/h (34). Ketamine has been known to cause uterine contraction in early pregnancy, but no effects in late pregnancy (26, 35). High doses of ketamine (10 mg/kg) were not proven to be teratogenic but two recent studies show that exposure of high doses of several hours may be associated with neuroapoptosis in fetal brains of monkeys; more than teratogenicity the concern for neurotoxicity remains high (36). Vasoactive Agents: Blood volume increases starting at week 4 of pregnancy and reaches 30-50% of baseline by 2834 weeks (1, 7, 37). At term, heart rate increases by 15-20 beats per minute; blood pressure decreases in mid-pregnancy (by 5-10 mmHg) but returns to pre-pregnancy range by term (1, 2, 37). Cardiac output (CO) rises by 15-25% by 8 weeks gestation and by term is up to 30-50% of baseline (1, 2). A gravid uterus (> 20 weeks) can compress the inferior vena cava (IVC), decreasing venous return and therefore CO (11). A wedge under the right pelvis or a rightward tilt will displace the uterus away from the IVC, theoretically alleviating the compression (1). The patient should be positioned tilted to the left (ideally at 27°) to relieve aortocaval compression (36, 37, 38). Uteroplacental blood flow is mostly dependent on MAP; vasopressors may be needed to maintain adequate MAP but they have shown to cause placental vasoconstriction (1). Vasopressors chosen in obstetrics are primarily those which are selective alpha 1 agonists (39). Phenylephrine, a purely alpha 1 agonist, has been studied in animals and has been shown to improve fetal acid-base status and increase maternal BP without compromising uterine blood flow (1, 30, 40). Norepinephrine and epinephrine may compromise uterine blood flow at exceedingly high doses (30). Dopamine has been used in a small case series for renal failure prevention in pre-eclampsia and one report documented no adverse effects for mother or infant (41). There is no data on vasopressin use in pregnancy and based on the limited literature, it is preferred to use phenylephrine as the initial agent and then consider norepinephrine or
6
epinephrine in refractory cases (30). However, when it comes to septic shock the Surviving Sepsis Guidelines remains the mainstay of therapy (42). Frequent fetal heart monitoring is recommended while the patient is on vasoactive drugs and assessing dynamic parameters of volume assessment (i.e. SVV, SVR, CO, CI, etc) via an arterial line should be highly considered. Resuscitation (i.e. CPR) for pregnant women is overall similar to usual basic life support (BLS) and adult advanced cardiac life support (ACLS). Pregnancy does not change the manner in which vasopressors or defibrillation is used (8, 37, 40). Challenges in these cases are confounded by lack of experience in this population. Less than one in 20,000 pregnant women have been reported to go into cardiac arrest, however there is an extensive variation of arrests from country to country (41, 43, 44). In-hospital BLS and ACLS algorithm should be implemented following cardiac arrest (36, 37). Continuous manual left uterine displacement (Class I AHA recommendation) should be used in patients with the uterus at or above the umbilicus until delivery can be accomplished (36, 41, 37, 43). Owing to body habitus, it may be difficult to oxygenate a patient with conventional face mask ventilation (8). Since hypoxia can occur rapidly, securing an airway is imperative; AHA recommends that interruptions in CPR be limited to 10 seconds however an exception can be made in the event of advanced airway placement. (36, 37, 38). Delivery of fetus improves outcomes of resuscitation of the mother; not only does it improve IVC circulation but it also helps to improve thoracic compliance making compressions more effective (41 43). Keep in mind that resuscitation is would always primarily directed at the mother in an emergency regardless of fetal gestation. Conclusion As there are many constraints in the management of OB patients, it is vastly important to understand the complexities (including basic physiologic changes) involved when caring for this population (7, Table 2, 44). Common disease states are associated with pregnancy and can mandate admission to the ICU: placental abruption, HELLP syndrome, amniotic fluid embolism, eclampsia, etc (12). We are often challenged by complex, multi-layer obstetric cases Often times we are challenged by the specifics, especially when the care becomes complicated (42). Mastery of the core principles of sedatives, analgesics, ventilator management, and vasoactive active agent use in the OB patient aims to ensure timely and safe implementation of therapy (1, 29, 32, 34, 37, 38, Table 3, Table 4). This review is in line with the FCCS/SCCM recommendations as it pertains to mechanical ventilation, vasoactive agents and airway management.
Tables: Table 1: Comparison of Previous Pregnancy Medical Risk Classification to New PLLR Guide (43, 44, 46, 47) Previous Pregnancy Medical Risk Classification
New PLLR Guide
Pregnancy risk letter categories (A, B, C, D, X) assigned.
Pregnancy risk letter categories eliminated.
7
Section 8.1 Pregnancy Section 8.2 Labor and Delivery
Combined to create one section: 8.1 Pregnancy ● ● ● ●
Section 8.3 Nursing Mothers
--
Pregnancy Exposure Registry Risk Summary Clinical Considerations Data
Becomes Section 8.2 Lactation ● Risk Summary ● Clinical Considerations ● Data New section added: 8.3 Females and Males of Reproductive Potential* ● Pregnancy ● Testing ● Contraception ● Infertility
PLLR = Pregnancy and Lactation Labeling Rule. *Only included when there are recommendations or requirements for pregnancy testing and/or contraception before,
during, or after drug therapy, and/or there are human and/or animal data suggesting drug-associated effects on fertility and/or preimplantation loss effects.
Table 2: Physiologic Changes of Pregnancy (7) Gastroenterology Gastroesophageal sphincter tone
Decrease
Gastric emptying
Decrease
Pulmonary Minute ventilation
Increase
Tidal Volume
Increase
Respiratory Rate
Increase
Oxygen consumption
Increase
PaO2
Increase
Functional residual capacity
Decrease
8
PaCO2
Decrease
Cardiovascular Cardiac Output
Increase
Heart Rate
Increase
Blood pressure
Decrease
Systemic vascular resistance
Decrease
Central venous pressure
Decrease
Pulmonary artery pressure
Decrease
Hematologic Blood volume
Increase
Plasma volume
Increase
Red blood cell volume
Increase
White blood cell volume
Increase
Coagulation factors
Increase
Hematocrit
Decrease
*Abbreviations: PaCO2 = arterial carbon dioxide tension; PaO2 = arterial oxygen tension.
Table 2: Sedatives/Analgesics (29, 32, 33, 48-53, 46-51 28, 31, 45-50) No Name 1
FDA Information
Dexmedetomidine 8.1: No studies in pregnant women to inform drug associated risks
Key Points -
Animal studies: No teratogenic effects were observed in a reproductive toxicology study conducted with dexmedetomidine dosed throughout organogenesis in rats with subcutaneous administration at doses approximately equal to the
-
Has anxiolytic, sedative, hypnotic, and analgesic properties Limited impact on the respiratory system Can reduce heart rate and blood pressure Atipamezole rapidly reversal agent but not routinely readily available
9
maximum recommended human dose 8.2: No information on presence in human milk, effect on breastfed infant, or on milk production Clinical consideration: A lactating woman may consider interrupting breastfeeding, pumping and discarding breast milk for 10 hours after receiving dexmedetomidine to minimize potential drug exposure infant. 8.3: No direct human information on male and female fertility 2
Propofol
8.1: There are no adequate and well-controlled studies in pregnant women. Animal Studies: Decreased pup survival with increased maternal mortality was observed with IV administration of propofol to pregnant rats either prior to mating and during early gestation or during late gestation and early lactation at exposures less than the human induction dose of 2.5 mg/kg
-
-
Produces rapid, profound sedation 1.5 to 2.5 mg/kg IV induces unconsciousness within 30 seconds 25 to 100 µg/kg/min achieves conscious sedation Recovery occurs within minutes Can cause decrease in systemic blood pressure In animal studies has not been shown to have teratogenic effects
Propofol not recommended for obstetrics, including cesarean sections. Propofol crosses the placenta. 8.2: Propofol has been reported to be excreted in human milk and the effects of oral absorption of small amounts are unknown. 8.3: No direct human information on male and female fertility
10
3
Fentanyl
8.1: Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates.
-
Animal Data: There was no evidence of teratogenicity reported. 8.2: Fentanyl is present in breast milk. There is insufficient information to determine the effects of fentanyl on the breastfed infant and effects of fentanyl on milk production.
-
Clinical Consideration: Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic or breast feeding is terminated.
Compared to morphine, fentanyl has a more rapid onset and 100 fold greater potency. 1-2 µg/kg causes a peak effect within 5 minutes and continues on for roughly 30 minutes Crosses placenta, if > 1ucg/kg, with reported incidences of respiratory depression Naloxone titrated in 0.04 mg IV increments every 2-3 minutes can reverse pruritus, nausea, & respiratory depression but may precipitate withdrawal symptoms.
8.3: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. Unknown whether the effects on fertility are reversible. 4
Ketamine
8.1: There are no adequate and well-controlled studies of ketamine in pregnant women. Animal Studies: Studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain
-
-
-
Increases heart rate, arterial blood pressure, and cardiac output (along with myocardial oxygen demand); not recommended in women with significant hypertension. Crosses the placenta; limited human data 30 seconds time of onset; 14.5 mg/kg for anesthesia induction. 0.2-0.75 mg/kg for procedural anesthesia.
11
of the offspring when used for longer than 3 hours
-
8.2: No documented data in breast-feeding mothers
Subanesthetic doses at 0.2 to 0.5 mg/kg IV occurs within 1 minute of administration and lasts 20 - 60 minutes
8.3: Adequate studies to evaluate the impact of ketamine on male or female fertility have not been conducted. 5
Midazolam
8.1: The use of injectable midazolam in obstetrics has not been evaluated in clinical studies. Midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression. 8.2: Midazolam is excreted in human milk. Maximum neonatal exposure is estimated at only 3% of maternal dose. 8.3: No human data information available on fertility. Animal studies: A reproduction study in male and female rats did not show any impairment of fertility at dosages up to 10 times the human IV dose of 0.35 mg/kg.
Decreases analgesic requirements and diminishes agitation without cardiovascular depression Crosses the placenta (less than diazepam), enters fetal circulation, and may contribute to neonatal depression; including mild sedation, hypotonia, reluctance to suck, apneic spells, cyanosis, impaired metabolic responses to stress, “floppy infant” syndrome, and marked neonatal withdrawal that can persist for hours to months after birth. Premedication prior to Csection may cause maternal amnesia
Table 3: Vasopressors (54-58, 52-56 51-55) No Name
FDA Information
Key Points
1
8.1: Human reproduction studies have not been conducted with norepinephrine.
-
Norepinephrine
8.2: Unknown if this drug is excreted in human milk.
-
May reduce uteroplacental blood flow High IV doses may decrease milk production and inhibit release of oxytocin
12
8.3: No human data information available on fertility.
2
Epinephrine
8.1: Epinephrine crosses the placenta. Potential risk to the fetus include fetal anoxia, spontaneous abortion, or both. Epinephrine usually inhibits spontaneous or oxytocin induced contractions of the pregnant human uterus and may delay the second stage of labor.
-
-
May cause fetal tachycardia May result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia. Avoid epinephrine during the second stage of labor.
Animal Studies: Epinephrine is teratogenic in rabbits, mice, and hamsters dosed during organogenesis. 8.2: Unknown whether epinephrine is excreted in human milk. 8.3: No human data information available on fertility. 3
Vasopressin
8.1: No adequate or wellcontrolled studies of vasopressin in pregnant women. May produce tonic uterine contractions that could threaten the continuation of pregnancy.
-
No data of use during pregnancy
8.2: Unknown whether vasopressin is excreted in human milk. Oral absorption by a nursing infant is unlikely because vasopressin is rapidly destroyed in the gastrointestinal tract. Advise a lactating woman to pump and discard breast milk for 1.5 hours after receiving vasopressin to minimize
13
exposure to infant. 8.3: No human data information available on fertility.
4
Phenylephrine
8.1: Unknown if phenylephrine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenylephrine does not appear to cause a decrease in placental perfusion sufficient to alter either the neonate Apgar scores or blood-gas status
-
Ideal for continuous infusion Will improve maternal BP without compromising uterine blood flow
-
May reduce uteroplacental blood flow Only used in a small group of cases for renal failure prevention in pre-eclampsia
8.2: Unknown if this drug is excreted in human milk. 8.3: No human data information available on fertility. 5
Dopamine
8.1: There are no adequate and well-controlled studies in pregnant women, and it is unknown if dopamine crosses the placenta.
-
8.2: Unknown if dopamine is excreted in human milk. 8.3: No human data information available on fertility. Note: It is prudent to adhere to the surviving sepsis guidelines in cases of septic shock. Table 4: Topic Summary
14
Topic Airway Management/Intubation
Study Design Multi-center RCT
Article, Authors Lee C, Jahr JS et al
Conclusion Sugammadex can be used as a reversal agent for non-depolarizing neuromuscular blocking agents
Mechanical Ventilation
Case series
Lapinsky SE, et al.
Ventilatory approach was similar to nonpregnant patients; mild hypercapnia is tolerated in pregnancy
Sedation/Analgesia
Case reports
Hilton G, et al
Hemodynamics/Vasoact ive agents
Cross-sectional study
Nakai Y, et al.
Prolonged propofol infusion may be associated with a reversible metabolic acidosis; Maternal prone position can provide complete relief of uterine compression of the large maternal vessels
15
Figures: Figure 1: The Food and Drug Administration of the Pregnancy and Lactation Labeling Rule (PLLR)
Resources: 1. Gaffney A. Critical care in pregnancy-is it different? Semin Perinatol. 2014;38:329–40. 2. Obstetrics & Gynecology: October 2016 - Volume 128 - Issue 4 - p e147–e154. doi: 10.1097/AOG.0000000000001710 3. Food and Drug Administration. Pregnancy and Lactation Labeling (Drugs) Final Rule.Fed Regist. 2014. Available at: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ ucm093307.htm. 4. Lamond NM, Freitag NE. Vertical Transmission of Listeria monocytogenes: Probing the Balance between Protection from Pathogens and Fetal Tolerance. Pathogens. 2018;7(2):52. Published 2018 May 25. doi:10.3390/pathogens7020052 5. D'Angelo R., Smiley R. M., Riley E. T., Segal S. Serious complications related to obstetric anesthesia: the serious complication repository project of the society for obstetric Anesthesia and Perinatology. Anesthesiology. 2014;120(6):1505–1512. doi: 10.1097/aln.0000000000000253. 6. Baldisseri MR, Plante LA. Fundamental Critical Care Support: Obstretrics. Mount Prospect, IL: Society of Critical Care Medicine; 2017 7. Bajwa SJS, Bajwa SK. Anaesthetic challenges and management during pregnancy: Strategies revisited. Anesthesia, Essays and Researches. 2013;7(2):160-167. doi:10.4103/0259-1162.118945. 8. Varon AJ, Smith CE. Essentials of Trauma Anesthesia. Cambridge, United Kingdom: Cambridge University Press; 2012: 288-298. 9. Dongare PA, Nataraj MS. Anaesthetic management of obstetric emergencies. Indian J Anaesth. 2018;62(9):704–709. doi:10.4103/ija.IJA_590_18
16
10. Mark Rollins, Jennifer Lucero; Overview of anesthetic considerations for Cesarean delivery, British Medical Bulletin, Volume 101, Issue 1, 1 March 2012, Pages 105–125. https://doi.org/10.1093/bmb/ldr050 11. Chaggar RS, Campbell JP (2017) The future of general anaesthesia in obstetrics. BJA Educ 17(3):83–79. doi: 10.1093/bjaed/mkw046 12. Lee C, Jahr JS, Candiotti KA, Warriner B, Zornow MH, Naguib M. Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine. Anesthesiology 2009; 110:1020-5. doi: 10.1097/ALN.0b013e31819dabb0. 13. Lapinsky SE, Rojas-Suarez JA, Crozier TM, Vasquez DN, Barrett N, Austin K. Mechanical ventilation in critically-ill pregnant women a case series. Int J Obstet Anesth. 2015;24(4):323–328. doi: 10.1016/j.ijoa.2015.06.009. 14. Cole DE, Taylor TL, Mccullough DM, Shoff CT, Derdak S. Acute respiratory distress syndrome in pregnancy. Crit Care Med. 2005; 33:S269-S278. 15. Nakai Y, Mine M, Nishio J, Maeda T, Imanaka M, Ogita S. Effects of maternal prone position on the umbilical arterial flow. Acta Obstet Gynecol Scand. 1998;77:967–969. doi: 10.1080/j.1600-0412.1998.771003. 16. Food and Drug Administration. FDA Drug Safety Communication. Available at: 2016. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communicationfda-review-results-new-warnings-about-using-general-anesthetics-and. Accessed May 7, 2019. 17. Food and Drug Administration. FDA Drug Safety Communication. Available at: 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communicationfda-approves-label-changes-use-general-anesthetic-and-sedation-drugs. Accessed May 7, 2019. 18. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-4. 19. Brambrink AM, Back SA, Riddle A, et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72(4):525–535. doi:10.1002/ana.23652. 20. Brambrink AM, Evers AS, Avidan MS, et al. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology. 2012;116(2):372–384. doi:10.1097/ALN.0b013e318242b2cd. 21. Briner A, Nikonenko I, De Roo M, Dayer A, Muller D, Vutskits L. Developmental Stagedependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology 2011;115:282-93. doi: 10.1097/ALN.0b013e318221fbbd. 22. Creeley CE, Dikranian KT, Dissen GA, Back SA, Olney JW, Brambrink AM. Isofluraneinduced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. Anesthesiology. 2014;120(3):626–638. doi:10.1097/ALN.0000000000000037. 23. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82.
17
24. Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 2011;33:220-30. doi: 10.1016/j.ntt.2011.01.001. 25. Scallet AC, Schmued LC, Slikker W Jr, Grunberg N, Faustino PJ, Davis H, et al. Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol Sci 2004;81:364-70. 26. Upadya M, Saneesh PJ. Anaesthesia for non-obstetric surgery during pregnancy. Indian J Anaesth. 2016;60(4):234–241. doi:10.4103/0019-5049.179445. 27. Rubin, R. Addressing barriers to inclusion of pregnant women in clinical trials. 2018; JAMA, 320,742– 744. doi: 10.1001/jama.2018.9989. 28. Haas DM, Marsh DJ, Dang DT, et al. Prescription and Other Medication Use in Pregnancy. Obstet Gynecol. 2018;131(5):789–798. doi:10.1097/AOG.0000000000002579 29. Buhimschi CS, Weiner CP. Medications in pregnancy and lactation: part 1. Teratology Obstetrics and Gynecology. 2009;113:166–188. doi: 10.1097/AOG.0b013e31818d6788. 30. Hockman RH, Kelsey J. Pregnancy in the ICU - Drug Implications. SCCM.org. http://myicucare.net/Communications/Critical-Connections/Archives/Pages/Pregnancyin-the-ICU---Drug-Implications.aspx. Published August 4, 2010. 31. Freyer AM. Drugs in Pregnancy and Lactation 8th Edition: A Reference Guide to Fetal and Neonatal Risk. Obstet Med. 2009;2(2):89. doi:10.1258/om.2009.090002 32. Hemphill S, McMenamin L, Bellamy MC, Hopkins PM. Propofol infusion syndrome: a structured literature review and analysis of published case reports. Br J Anaesth. 2019;122(4):448–459. doi:10.1016/j.bja.2018.12.025 33. Hilton G, et al. Prolonged propofol infusions in pregnant neurosurgical patients. J Neurosurg Anesthesiol. 2007; 19:67-68. doi: 10.1097/ANA.0b013e31802b31c8 34. Toledano RD, Kodali BS, Camann WR. Anesthesia drugs in the obstetric and gynecologic practice. Rev Obstet Gynecol. 2009;2(2):93-100. 35. Oats JN, Vasey DP, Waldron BA. Effects of ketamine on the pregnant uterus. Br J Anaesth. 1979;51:1163–6. 36. Pinyavat T, Warner DO, Flick RP, et al. Summary of the update session on clinical neurotoxicity studies. J Neurosurg Anesthesiol 2016;28:356-360 37. Jeejeebhoy FM, Zelop CM, Lipman S, et al; for American Heart Association Emergency Cardiovascular Care Committee, Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Cardiovascular Diseases in the Young, and Council on Clinical Cardiology. Cardiac arrest in pregnancy: a scientific statement from the American Heart Association. Circulation. 2015;132(18):1747–1773. 38. Campbell TA, Sanson TG. Cardiac arrest and pregnancy. J Emerg Trauma Shock. 2009;2(1):34–42. doi:10.4103/0974-2700.43586. 39. Nag DS, Samaddar DP, Chatterjee A, Kumar H, Dembla A. Vasopressors in obstetric anesthesia: A current perspective. World J Clin Cases. 2015;3(1):58–64. doi:10.12998/wjcc.v3.i1.58. 40. Practice Guidelines for Obstetric Anesthesia: An Updated Report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia and the Society for Obstetric Anesthesia and Perinatology. Anesthesiology 2016;124(2):270-300. doi: 10.1097/ALN.0000000000000935.
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41. Kirshon B, et al. Effects of low-dose dopamine therapy in the oliguric patient with preeclampsia. Am J Obstet Gynecol. 1988; 159:604-607. 42. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304–377. 43. Truhlář A, Deakin CD, Soar J, Khalifa GEA, Alfonzo A, Bierens JJLM, et al. European resuscitation council guidelines for resuscitation 2015. Resuscitation. 2015;95:148–201. doi: 10.1016/j.resuscitation.2015.07.017. 44. Lipman S, Cohen S, Einav S, et al. The Society for Obstetric Anesthesia and Perinatology consensus statement on the management of cardiac arrest in pregnancy. Anesth Analg. 2014;118(5):1003–1016. doi: doi: 10.1213/ANE.0000000000000171. 45. Soubra SH, Guntupalli KK. Critical illness in pregnancy: an overview. Crit Care Med 2005;33(10 Suppl):S248–55. doi:10.1097/01.CCM.0000183159.31378.6A. 46. Pernia S, DeMaagd G. The New Pregnancy and Lactation Labeling Rule. P T. 2016;41(11):713–715. 47. Food and Drug Administration. Content and format of labeling for human prescription drug and biological products: requirements for pregnancy and lactation labeling. Fed Regist. 2014;79(233):72064–72103. Available at: www.gpo.gov/fdsys/pkg/FR-2014-1204/pdf/2014-28241.pdf. 48. Food and Drug Administration. Center for Drug Evaluation and Research: Dexmedetomidine. 2015. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206628Orig1s000OtherR.pdf. Accessed April 16, 2019. 49. Food and Drug Administration. Center for Drug Evaluation and Research: Fentanyl. 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016619s038lbl.pdf. Accessed April 16, 2019. 50. Food and Drug Administration. Center for Drug Evaluation and Research: Propofol. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019627s066lbl.pdf. Accessed April 16, 2019. 51. Food and Drug Administration. Center for Drug Evaluation and Research: Ketamine. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016812s040lbl.pdf. Accessed April 16, 2019. 52. Food and Drug Administration. Center for Drug Evaluation and Research: Midazolam. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208878Orig1s000lbl.pdf. Accessed April 16, 2019. 53. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):521–546. doi:10.1097/AAP.0000000000000808
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54. Food and Drug Administration. Center for Drug Evaluation and Research: Phenylephrine. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203826s000lbl.pdf 55. Food and Drug Administration. Center for Drug Evaluation and Research: Dopamine. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019615s024lbl.pdf. Accessed April 16, 2019. 56. Food and Drug Administration. Center for Drug Evaluation and Research: Levophed. 2007. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/007513Orig1s024lbl.pdf. Accessed April 16, 2019. 57. Food and Drug Administration. Center for Drug Evaluation and Research: Epinephrine. Available at: 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205029s004lbl.pdf. Accessed April 16, 2019. 58. Food and Drug Administration. Center for Drug Evaluation and Research: Vasopressin. Available at: 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/204485Orig1s004.pdf. Accessed April 16, 2019.
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Highlights: • • • •
A multidisciplinary approach is optimal for the long term care of a parous ICU patient Therapy, in an emergency, should be guided primarily toward the mother even though the fetus is commonly thought about. The new pregnancy and lactation labeling rule should be familiarized as the category labeling has been abandoned by the Food and Drug Administration. Open communication with your neonatologist/pediatrician is necessary when using sedatives, analgesics, and vasoactive agents for long periods of time.
Conflicts of Interest: The authors declare that there is no conflict of interest regarding the publication of this article.