Hello, my name is Elizabeth Farrington, and I am a pediatric ICU pharmacist at New Hanover Regional Medical Center in Wilmington, North Carolina. I'm speaking in a session, COVID-19 and the pregnant patient, and I will be speaking about medication selection and management and the patient with COVID-19. We have four goals and objectives for our presentation today. Consider medication delivery to the mother and possible beneficial or detrimental effects to the baby. Assure appropriate corticosteroid dosing in pregnant mothers with COVID-19. We need to discuss optimal agents for analgesia, sedation, and neuromuscular blockade in the pregnant patient and the adult ICU, and understand the risk and benefits of cardiovascular medications in pregnant patients with COVID-19. There are several key concepts that allow a medication to pass from the mother through the placenta to the fetus. Lipophilic drugs will readily cross the placenta. Drugs that are non-ionized at physiologic pH will cross more readily than either acidic or basic medications as they can pass by passive diffusion. Drugs that should not readily cross are those that are highly protein bound or have large molecular weights. The previous speaker spoke about specific COVID medications to be used in the pregnant patient in the ICU. Remembering that dexamethasone 6mg, either IV or PO, is recommended by the NIH guidelines to be given Q24 hours for 10 days or until hospital discharge. This is for all comers with COVID-19. The big things we need to think about though in the pregnant woman is what do we do if they have a patient who has a neonate or a fetus between 24 and 33 weeks of gestation and they are at imminent chance of delivery. There are two drugs recommended by the American College of OBGYN to be given to the mother to enhance lung maturity or increase surfactant production in that neonate so that they have a better chance of survival once delivered. One is betamethasone 12mg IM Q24 hours times 2 doses or dexamethasone 6mg IM Q12 hours for 4 doses. Either of these medications are equally efficacious in improving survival in neonates by increasing production of surfactant. If the neonate of the delivery of the neonate is imminent and the neonate is between 24 and 33 weeks of gestation, we need to consider altered doses of corticosteroids. Most likely since we are already on dexamethasone, increasing that dose to 6mg Q12 for 4 doses. If their perfusion is poor due to how they are doing with their COVID, we can give that intravenously every 12 hours for 4 doses although the IM regimen is the one that has been most extensively studied. When considering analgesia in the pregnant female, we need to talk about which meds are most safe. Pain should always be treated first with non-opioids if possible to maintain pain control. IV, PO, or rectal acetaminophen can be administered. If you remember, acetaminophen actually has prolonged duration in pregnant women due to decreased metabolism. Use of non-steroidal anti-inflammatory drugs such as Ketorolac, ibuprofen, and naproxen should be avoided as they pose a risk to the fetus. Remember closure of the ductus arteriosus can occur if patients are administered non-steroidal anti-inflammatory agents. The ductus is critical to maintaining fetal circulation so we need to avoid the use of NSAIDs in the pregnant patient. Methionine and fentanyl transfer readily to the placenta and subsequently to the fetus. Fentanyl is highly lipophilic so dosing should be dosed on ideal body weight to avoid prolonged effects in the neonate. Morphine, however, has active metabolites M3 and M6 glucuronide that have longer half-lives than morphine itself. They may accumulate in the neonate. Hadromorphone has the least amount of safety data in the pregnant patient but the drug has been reported to accumulate in breast milk, therefore would be our last choice in the pregnant patient. The PADIS guidelines recommend four sedatives to be used in the critically ill adult patient. Propofol, benzodiazepines, dexmedetomidine, and ketamine. We'll talk about each of these individually and where they fit in the pregnant patient. Propofol is highly lipophilic, thus should be dosed again on ideal body weight. Pregnant women may require higher doses to achieve adequate sedation as Propofol has been reported to have enhanced elimination and the increased total body water will increase the volume of distribution of Propofol. Hypotension is our rate-limiting factor in using Propofol because the last thing we want in a pregnant woman is hypotension because then the fetus would also suffer from hypotension or poor perfusion. Pregnant women have been discouraged with all of our most recent guidelines as they are most highly associated with delirium. So they should not be our first choice in any patient in the ICU, however they should be avoided in pregnant women because they can accumulate in the fetus and cause sloppy infant syndrome when they're born. Lorazepam, in addition, contains propylene glycol because the drug is not very water soluble and has to be dissolved in propylene glycol. This agent can accumulate in the neonate because they only have 1-2% of their alcohol dehydrogenase. Dexmedetomidine has not been shown to cross the placenta or produce any fetal abnormalities in the pregnant female. At standard dosing of 0.2-1.4 micrograms per kilogram per hour, it probably is the safest agent we have to use in the pregnant female. Ketamine can cause tachycardia, hypertension, reduce uterine tone, and potentially reduce uterine blood flow. Single doses for intubation may be considered in the pregnant female, but not if we're close to delivery. Concern exists with the use of continuous infusions and they should be avoided. Non-depolarizing neuromuscular blockers are preferred for intubation in the pregnant patient and rocuronium is considered safe in pregnancy. Succinylcholine, which is the historic gold standard for rapid-sequence intubation, is typically avoided in the pregnant female because of their increased volume of distribution leading to larger doses being required and pregnant females have a decreased production of plasma cholinesterases, making the elimination of succinylcholine undetermined. This makes the use of the drug challenging. For continuous infusions, becuronium and astrocurium have the most safety data. With a lack of fetal exposure or the least amount of fetal exposure, accumulation of neuromuscular blockers may occur in the neonate, so when we need to use a neuromuscular blocker, we should use them for the shortest amount of time possible. If the mother, however, is receiving magnesium and a magnesium infusion for preeclampsia, it will potentiate the effects of non-depolarizing neuromuscular blockers and this may be the one place where we should use succinylcholine to intubate our patient. Many cardiovascular complications can occur in the pregnant female. If we need to have an agent for rate control, we should avoid amiodarone because feel effects, including congenital goiter and hypo or hyperthyroidism have been reported, which is not surprising because we can see hypo or hyperthyroidism with normal use in adult or pediatric patients. Diuretics, furosemide, and hydrochlorothiazide have been used with no congenital side effects. However, hydrochlorothiazide may cause maternal hyperglycemia, fetal hypoglycemia, decreased placental perfusion, and decreased breast milk production. Clearly, if the mother is on hydrochlorothiazide when she becomes pregnant, that drug may be continued. However, we should not initiate hydrochlorothiazide use during pregnancy. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated in the pregnant female. This is for two reasons. Skeletal anomalies have been reported, as well as adverse renal effects, anywhere from renal agenesis to just renal scarring and decreased renal perfusion. Calcium channel blockers can be used safely in pregnant women. Sialticin would be our preferred agent for ventricular rate control, and verapamil, nifedipine, and nicardipine have been used safely without adverse effects in the pregnant female. There are many physiologic changes that occur in the pregnant female, one being increased plasma volume and the second being increased glomerular filtration rate. Beta-lactam antibiotics are affected by both of these effects, leading to decreased serum levels of beta-lactam antibiotics and more rapid renal clearance. Therefore, we need to consider if our patient is not improving that we might need to use higher doses of beta-lactam antibiotics in the pregnant female to treat infections. Therefore, we should adjust the dose based on clinical response. Some clinicians have recommended, for example, for cefepime, that even though we may be treating something that we historically would use 2 grams Q12, that we use the increased dose of 2 grams intravenously every 8 hours. Others have recommended that meningitic doses of beta-lactam antibiotics be used, even though we're not treating meningitis, to counteract the changes in plasma volume and renal clearance. We have only discussed the highlights of some medications that might be used in the adult ICU when taking care of a pregnant patient. Just to summarize the other physiologic changes and how they might affect drug pharmacokinetics, we see delayed gastric emptying and increased gastric pH. This leads to decreased drug bioavailability and delayed time for peak levels after oral administration. The increased cardiac output that we see in pregnant females will lead to increased hepatic blood flow. Therefore, increased elimination of drugs that have a high extraction through the liver. The increase in total body water and extracellular fluid will lead to an altered volume of distribution, specifically increased volume of distribution for hydrophobic drugs. We also see an increase in the fat compartment. This will lead to decreased elimination of lipid-soluble drugs and an increased volume of distribution for hydrophobic drugs. The increased renal blood flow and glomerular filtration rate will lead to increased renal clearance. Decreased plasma albumin concentration will lead to increased refraction of drugs. And we see altered cytochrome P450 and UGT activity, specifically decreased UGT activity will lead to altered oral bioavailability and then altered cytochrome P450 can alter hepatic elimination. In conclusion, there are many medications that we might use to take care of a pregnant patient who presents to our adult ICUs with COVID-19. Choice of medication should be based on the need of the mother, but if possible, consideration of the effects to the fetus is paramount to the safe delivery of the neonate. Thank you for your attention.

medication selection

pregnant patients

COVID-19

corticosteroid dosing

fetus