By: Ashley Jose, PharmD Candidate Class of 2021; St. Louis College of Pharmacy
Mentor: Emily Walsh, PharmD; Adult Multispecialty Clinics and University of Iowa Hospitals and Clinics
Venous thromboembolism (VTE) is the second most common cause of mortality in patients with cancer and the most frequent complication of malignancy.1 The estimated annual incidence of VTE among the general population is 1 to 2 per 1,000 people.1 In patients with cancer-associated thrombosis (CAT), the estimated risk of VTE is four to six times higher, and overall survival rates are much lower with significantly worse prognosis1. This increased risk of VTE is often multifactorial and can be caused by numerous patient and cancer-related factors, such as immobility, site and severity of cancer, stage and histology of the tumor, and treatment.1,2 Patients with CAT are also at a heightened risk of bleeding due to malignancy and anticoagulation. The economic burden of CAT is very high, with health care costs 40-50% higher than patients without CAT.1
Until recently, the standard of care for the treatment of CAT according to multiple practice guidelines has been low molecular weight heparin (LMWH), which was found to reduce VTE recurrence in cancer patients in various studies. The CLOT trial compared the efficacy of LMWH to oral vitamin K antagonist (VKA) treatment in preventing recurrence of thrombosis in patients with cancer.3 Patients were randomized to receive weight-based dalteparin or warfarin with an INR goal of 2-3 for 6 months. Dalteparin was found to significantly reduce the risk of recurrent VTE without increasing the risk of bleeding. LMWHs have a fast onset of action, reach steady state quickly, and avoid the need for oral absorption, which is especially useful for patients with poor oral intake. However, LMWH may cause adherence issues due to subcutaneous route of administration.
Direct oral anticoagulants (DOACs) have become the standard of care for the treatment of VTE in non-cancer patients based on efficacy and safety observed in landmark clinical trials. DOACs are a favorable treatment option for VTE as they do not require laboratory monitoring and have fewer drug-drug interactions than oral VKA's. However, landmark trials assessing the efficacy of DOACs for the treatment of VTE in the general population had a low enrollment of cancer patients, thus requiring further investigation of the use of these agents for the treatment of CAT. Recent clinical trials have been conducted to attempt to determine the place in therapy for DOACs for the treatment of CAT.
Clinical Trial Review
The SELECT-D trial was a multicenter, randomized, open-label, pilot trial that assessed the efficacy and safety of rivaroxaban for treatment of CAT.4 Patients with active VTE were randomized to rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg once daily or dalteparin 200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6 for a total of 6 months. The most prevalent cancers were colorectal, lung, and breast cancer. The cumulative rate of recurrent VTE was 4% for patients in the rivaroxaban group compared to 11% in the dalteparin group (HR, 0.43; 95% CI, 0.19 to 0.99). The primary safety endpoint of major bleeding occurred in 11 patients receiving rivaroxaban and 6 patients receiving dalteparin, with a cumulative major bleed rate at 6 months of 6% and 4%, respectively, (HR, 1.83; 95% CI, 0.68 to 4.96). More major bleeding occurred in patients receiving rivaroxaban, especially patients with gastrointestinal or esophageal cancer. Significantly more clinically relevant non-major bleeding (CRNMB) occurred in patients receiving rivaroxaban compared to dalteparin (13 vs 4%, HR 3.76, 95% CI 1.63 to 8.69). This trial provided evidence that patients receiving rivaroxaban had significantly fewer episodes of recurrent VTE at the expense of increased bleeding, especially in patients with esophageal cancer.
HOKUSAI-VTE trial was an open-label, non-inferiority trial that assessed the efficacy and safety of edoxaban in patients with VTE and cancer.5 Patients were randomized to receive either edoxaban 60 mg daily or subcutaneous dalteparin 200 IU/kg once daily for 30 days, then 150 UI/kg once daily and followed for 12 months. The primary composite outcome of recurrent VTE or major bleed occurred in 67 patients (12.8%) receiving edoxaban compared to 71 patients (13.5%) receiving dalteparin (HR, 0.97; 95% CI 0.70 to 1.36; P=0.006 for non-inferiority, 0.87 for superiority). There was no difference between edoxaban and dalteparin in regards to recurrent VTE (7.9 vs 11.3%, p = 0.09), but there was significantly more major bleeding (6.9 vs 4%, p = 0.04), especially gastrointestinal bleeding in the setting of gastrointestinal cancer. This trial provided evidence that edoxaban is non-inferior to treatment with dalteparin for the composite outcome of recurrent VTE or major bleeding for up to 12 months. Similar to the SELECT- D trial, patients in the edoxaban group were found to have higher rates of major bleeding, especially bleeds that were gastrointestinal in nature and occurring in patients with gastrointestinal malignancy
The Caravaggio trial was a multinational, randomized, open-label, non-inferiority trial aimed to assess the safety and efficacy of apixaban in patients with CAT.6 Patients with active VTE were randomized to apixaban 10 mg twice daily for seven days, followed by 5 mg twice daily or dalteparin 200 units/kg once daily for one month, followed by 150 units/kg once daily for a total of 6 months. This trial mainly included advanced active cancers and had the highest amount of patients with ECOG performance status score of 1. The most common cancer types included were gastrointestinal, colorectal, and lung cancer. The primary outcome of recurrent VTE occurred in 32 patients (5.6%) in the apixaban group vs 46 patients (7.9%) in the dalteparin group (HR, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for non-inferiority; P=0.09 for superiority). The primary safety outcome of major bleeding occurred in 22 patients (3.8%) receiving apixaban compared to 23 patients (4%) receiving dalteparin (p = 0.60). The authors of the Caravaggio trial concluded that apixaban is non-inferior to subcutaneous dalteparin for preventing recurrent VTE in cancer patients with no difference in bleeding. This trial uniquely had less frequency of major and gastrointestinal major gastrointestinal bleeding compared to Hokusai-VTE and SELECT-D.
Takeaways and Recommendations
Based on the results of recently published clinical trials discussed above, DOACs appear to be efficacious in the treatment of CAT. However, rivaroxaban and edoxaban appear to have an increased risk of bleeding, especially those that are gastrointestinal in nature in those with gastrointestinal cancer.4-5 Some clinical practice guidelines for the treatment of cancer associated thrombosis have been updated based on the results of these trials. The CHEST guidelines, last updated in 2016, recommend LMWH over oral VKAs or any DOACs for the treatment of CAT.7 The 2020 ASCO guidelines were recently updated and recommend use of LMWH, edoxaban, or rivaroxaban for the treatment of CAT.8 NCCN 2020 guidelines recommend the use of DOACs, particularly apixaban, rivaroxaban and edoxaban, but suggest using LMWH in patients with CAT with gastric or gastroesophageal lesions.8-9 Both NCCN and CHEST guidelines recommend at least 3 months of treatment or as long as active cancer or cancer therapy.7,9
There are questions that remain regarding the use of DOACs for treatment of CAT. Currently, no head to head clinical trials are available to assess which DOAC is superior in the treatment of CAT. The duration of anticoagulation differed between all three trials, ranging from six to twelve months, which limits our ability to determine long term safety and efficacy. Cohort studies have found that the risk of recurrent VTE in CAT can run beyond 6 months, therefore a duration longer than 6 months may be beneficial after weighing the risk of recurrent VTE versus risk of bleed.10 More information is also needed pertaining to efficacy and safety of treatment across cancer type and severity, as the patient populations in these studies were diverse.
Patient preference, cancer specific factors, and patient specific factors should be utilized to select an appropriate anticoagulant for the treatment of CAT. DOACs appear to have a place in therapy for CAT and are conveniently dosed and administered. However, DOACs can be more costly, have a limited place in therapy in those with renal insufficiency and should be used very cautiously in those at increased risk of bleeding or in those with GI malignancy.10 LMWH can still be considered as a viable alternative, especially in those with cost concerns, concerns related to GI absorption, or difficulty with oral intake.
By: Meredith Vigneaux, PharmD; Mercy Hospital Springfield
The number one cause of death for patients with diabetes is due to cardiovascular (CV) disease, therefore lowering hemoglobin A1c with a medication that does not increase CV disease risk has become a central focus of diabetes treatment. Metformin was the first glucose lowering drug to demonstrate a positive effect on CV risk in the United Kingdom Prospective Diabetes Study (UKPDS), which ended in 1997.1,2 Since the correlation between the use of rosiglitazone3,4,5 and an increase in cardiovascular (CV) risk, specifically increased occurrence of heart failure (HF) hospitalizations, the FDA has recommended that new diabetes medications “demonstrate that the therapy will not result in an unacceptable increase in CV risk”.6 These trials are referred to as the Cardiovascular Outcomes Trials (CVOT). From 2008 to 2019 the FDA has required CVOT to be completed on new antihyperglycemic medications. They are currently reviewing the need for CVOT and are proposing adjusting this requirement in the near future.7
Cardiovascular Outcome Trials by Class
CVOT are designed to initially evaluate cardiovascular harm. If the medication shows no harm compared to placebo, when added to standard of care, the medication can then be evaluated for cardiovascular benefit if the study is powered for superiority. The three-part major adverse cardiovascular events (MACE) is composed of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke and is frequently the primary endpoint for CVOT. A four-part MACE endpoint has been used in some CVOT and adds hospitalization for unstable angina as the fourth part of the composite. Results from several CVOT trials are summarized in Table 1 and trials with significant outcomes are presented in more detail.
Dipeptidyl Peptidase-4 Inhibitors (DPP4)
Dipeptidyl peptidase-4 inhibitors work by inhibiting dipeptidyl peptidase (DPP4), therefore prolonging incretin levels, which helps regulate glucose homeostasis by increasing insulin synthesis and insulin release from beta cells. They also work by decreasing glucagon secretion from alpha cells. Cardiovascular benefit has not been demonstrated with DDP4 agents and possible HF risk has not shown to be a class effect.
The Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care (EXAMINE) trial, evaluating a three-part MACE in 5,380 patients with Type 2 Diabetes Mellitus (T2DM) and preexisting CV disease. 17 There was a 0.5% difference in MACE with alogliptin treatment compared to placebo. No statistically significant difference was seen in the alogliptin versus placebo for the primary endpoint, therefore no cardiovascular benefit was observed. There was an increase in hospitalization from heart failure in the alogliptin group that was statistically significant with a 0.6% difference in heart failure hospitalizations between the treatment group and placebo. Of further interest, there was a 0.3% difference in patients who had a history of heart failure and a 0.9% difference in patients who had no history of hospitalizations due to heart failure.33
In the Saxagliptin Assessment of Vascular Outcomes in Patients with Diabetes Mellitus (SAVOR) Thrombolysis in Myocardial Infarction (TIMI) 53 trial, the primary outcome was three-part MACE in 16,492 participants. 18 Patients had T2DM with multiple risk factors for CV disease or a history of CV disease. Saxagliptin was compared to placebo and there was a 0.1% difference in MACE, which was not statistically significant, therefore no cardiovascular benefit was observed. There was an observed increase in heart failure hospitalizations that was not statistically significant in the patients receiving saxagliptin (0.7% difference in heart failure hospitalizations between the two groups).
The primary outcome of a four-part MACE with sitagliptin was evaluated in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) trial, in 14,671 participants.19 Patients had T2DM with Acute Coronary Syndrome (ACS) within 15-90 days before randomization. There was a 0.2% difference in MACE with sitagliptin treatment compared to placebo. No statistically significant difference was seen in sitagliptin versus placebo for the primary endpoint; therefore, no cardiovascular benefit was observed. There was no statistically significant increase in heart failure hospitalization in the patients receiving sitagliptin (0.1% difference in heart failure hospitalizations between the two groups).
Glucagon-like peptide-1 (GLP-1)
Glucagon-like peptide-1 acts as an incretin-like hormone which increases glucose-dependent insulin secretion, decreases inappropriate glucagon secretion, increases beta cell growth and replication, decreases gastric emptying, and increases satiety. With GLP-1 agents, a cardiovascular benefit has not been demonstrated as a class effect, but three of these agents have proven cardiovascular benefit.
The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, the primary outcome was four-part MACE in 6,068 participants.20,21 Patients had T2DM and an acute coronary event within 180 days before screening. There was a 0.2% difference in MACE with lixisenatide treatment compared to placebo. No statistically significant difference was seen in lixisenatide versus placebo for the primary endpoint; therefore, no cardiovascular benefit was observed. Lixisenatide provided an average weight loss of 0.6 kg. Of note, there was a decrease in hospitalization from heart failure observed in the lixisenatide group (0.5% difference between lixisenatide and placebo). It is important to note that of the GLP-1 CVOTs, this is the trial with the highest risk study population as they had recently experienced a cardiac event.
In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, the primary outcome was three-part MACE in 14,752 participants.22 Patients had T2DM with or without preexisting CV disease. There was a 0.8% difference in MACE with exenatide treatment compared to placebo. No statistically significant difference was seen in exenatide versus placebo for the primary endpoint; therefore, no cardiovascular benefit was observed. Exenatide provided an average weight loss of 1.27kg.
In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, the primary outcome was three-part MACE in 9,340 participants.23,24 Patients had T2DM and kidney disease, HF, or CV disease and were greater than 50 years of age, or the patients had T2DM and had more than one CV risk factor and were greater than 60 years of age. There was a 1.9% difference in MACE with liraglutide treatment compared to placebo. Superiority was seen with liraglutide versus placebo, therefore cardiovascular benefit observed. Patients who were receiving liraglutide required less insulin. The superiority outcome was mainly driven by a decrease in death from cardiovascular cause and fatal or non-fatal myocardial infarction. Liraglutide provided an average weight loss of 5kg.
In the Peptide Innovation for Early Diabetes Treatment (PIONEER-6) trial, the primary outcome was three-part MACE in 3,176 participants.25 Patients had T2DM and Chronic Kidney Disease (CKD) or CV disease and were greater than 50 years of age, or the patients had T2DM and had more than one CV risk factor and were greater than 60 years of age. There was a 1% difference in MACE with oral semaglutide treatment compared to placebo. No statistically significant difference was seen in oral semaglutide versus placebo for the primary endpoint; therefore, no cardiovascular benefit was observed. Oral semaglutide provided an average A1c decrease of 1% and an average weight loss of 4.2kg. Semaglutide’s mechanism of action in an oral option may be a beneficial option in patients who require additional A1c lowering and post-prandial glucose coverage, who are not willing to do an injection, and do not have additional CV risk.
In the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial, the primary outcome was three-part MACE in 9,901 participants.26 Patients had T2DM and were at least age greater than 50 years with previous CV disease; or patients had T2DM and were at least age greater than 60 years with two cardiovascular risk factors. There was a 1.4% difference in MACE with dulaglutide treatment compared to placebo. There was superiority with dulaglutide over placebo; therefore, cardiovascular benefit was observed. The superiority outcome was mainly driven by a decrease in non-fatal and fatal stroke. Dulaglutide provided an average weight loss of 3 kg.
In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) ,the primary outcome was three-part MACE in 3,297 participants.27 Patients had T2DM and CKD, HF, or CV disease and were greater than 50 years of age, or the patients had T2DM and had more than one CV risk factor and were greater than 60 years of age. There was a 2.3% difference in MACE with subcutaneous semaglutide treatment compared to placebo. Semaglutide was superior to placebo, therefore cardiovascular benefit was observed. The superiority outcome was mainly driven by a decrease in nonfatal stroke and revascularization. Patients who were receiving semaglutide lost an average of 4.2kg. This was the second once weekly GLP-1 approved with cardiovascular benefit. Semaglutide has been studied head to head with Trulicity and was found to have greater A1c lowering and weight loss.34
Sodium Glucose Transport-2 (SGLT-2) Inhibitors
The sodium glucose transport-2 (SGLT-2) inhibitors work by inhibiting SGLT-2 in the proximal renal tubule and reduces glucose reabsorption from the tubular lumen and ultimately reduces blood glucose concentrations. The cardiovascular benefit is considered a class effect of the SGLT-2 inhibitors; however the individual agents show variability in the type of cardiovascular benefit. While each of the SGLT-2 medications have renal dose adjustments, they are being studied in the CKD population for possible renal protection and utility in preventing renal death.
In the CANagliflozin cardioVascular Assessment Study (CANVAS) trial, the primary outcome was three-part MACE in 10,142 participants. 30 Patients had T2DM and preexisting CV disease who were greater than 30 years old or patients who had T2DM and were greater than 50 years old with more than two CV risk factors. Superiority was found with canagliflozin compared to placebo, therefore cardiovascular benefit was seen. Canagliflozin cardiovascular benefit was statistically significant for Atherosclerotic Cardiovascular Disease (ASCVD). While the primary outcome was found to be statistically significant, when evaluated as a subgroup analysis of death from cardiovascular cause, nonfatal myocardial infarction and nonfatal stroke, none of the groups had statistical significance. There is question regarding the validity of the primary outcome having statistical significance in the primary outcome because the subgroups did not have statistical significance. However, in a separate study, canagliflozin has been studied in CKD and was shown to be statistically significant in reducing renal or cardiovascular death.35
In the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE) Thrombolysis In Myocardial Infarction (TIMI) 58 trial, the primary outcome was three-part MACE and composite of cardiovascular death or hospitalization for heart failure in 17,276 participants. 31 Patients had T2DM and were at least age of 40 years old and had established CV disease or risk factors for CV disease. There was a 0.6% difference in MACE with dapagliflozin treatment compared to placebo. The decreased rate in MACE was not statistically significant. There was a 0.9% difference in composite of cardiovascular death or hospitalization for heart failure for the treatment group, this outcome was shown to be statistically significant. Superiority with dapagliflozin compared to placebo, therefore cardiovascular benefit was seen. The superiority outcome was primarily driven by a decrease in hospitalizations from heart failure. Dapagliflozin cardiovascular benefit was statistically significant for HF. In a follow up study evaluating patients with New York Heart Association Class II, III, or IV heart failure with an ejection fraction of 40% or less receiving placebo or dapagliflozin, it was found that dapagliflozin group had a decreased risk of worsening heart failure.36 Dapagliflozin now has an FDA indication for reducing the risk of cardiovascular death for patients with heart failure with reduced ejection fraction or preserved ejection fraction.
In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG) trial, the primary outcome was three-part MACE in 7,020 participants.32 Patients had T2DM with preexisting CV disease and a Body Mass Index (BMI) less than 45 kg/m2 and eGFR greater than 30mL/min/1.73m2. There was a 1.5% difference in MACE in patients treated with empagliflozin compared to the placebo treatment group. Superiority with empagliflozin compared to placebo, therefore cardiovascular benefit was seen. Empagliflozin cardiovascular benefit was statistically significant for ASCVD and a decrease in hospitalizations from heart failure (HHF). A decrease in HHF was the driving outcome in the combined ASCVD and HF benefit outcome.
Current Guideline Recommendations
Metformin continues to be first line therapy per the American Diabetes Association (ADA)37 and the American Association of Clinical Endocrinologists (AACE)38 due to its robust CV safety data in comparison with sulfonylureas from the UKPDS trials. Along with the addition of lifestyle modifications with metformin, ADA recommends use of a GLP-1 or SGLT-2 with proven cardiovascular benefit and additional therapy to achieve goal A1c in patients who have established ASCVD. AACE also recommends addition of GLP-1 or SGLT-2 to metformin if coronary heart disease (CHD) is present. The American Heart Association (AHA)39 and the American College of Cardiology (ACC) recommend consideration of addition of cardiovascular protective SGLT-2 or GLP-1 to metformin in patients whose A1c is greater than 7% and have CV risk factors.
By: Kyle Stupca, PharmD; Mercy Hospital - Springfield
The incidence of atrial fibrillation (AF) in patients with acute coronary syndromes (ACS) ranges from 10% to 20% and increases with patient age and severity of myocardial infarction (MI). Subsequently, AF is associated with increased in-hospital mortality, 30-day mortality, and 1-year mortality.1 Stroke rates are higher in patients with MI and AF than those without AF with the incidence being 3.1% in patients with AF compared to 1.3% in patients without AF.2 Patients treated for ACS normally require dual antiplatelet therapy (DAPT) with aspirin (ASA) plus a platelet P2Y12 inhibitor such as clopidogrel, ticagrelor, or prasugrel. DAPT has been proven to reduce the incidence of recurrent ischemic events and stent thrombosis but is less effective in reducing the incidence of cardioembolic stroke associated with AF.3,4 As a result, patients with AF may require the addition of an anticoagulant such as warfarin or a direct oral anticoagulant (DOAC) for the primary prevention of stroke if they are at a high risk.5 The resulting regimen consists of DAPT with the addition of warfarin or a DOAC and is otherwise known as triple antithrombotic therapy. Although patients are at an increased risk of thrombosis as a result of AF, initiating triple antithrombotic therapy comes with its own set of risks, the most concerning of which is clinically significant bleeding. Because of this, it is important to fully evaluate the benefits and risks of these regimens before recommending them for our patients.
There have been numerous important trials in recent years evaluating the use of triple antithrombotic therapy compared to some form of double therapy with an anticoagulant and a single antiplatelet agent. Several of these trials were utilized when formulating current guideline recommendations for the management of patients with AF and ACS.
The use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events in adult patients receiving oral anticoagulants (OAC) and undergoing percutaneous coronary intervention (PCI).
Six weeks of triple antithrombotic therapy, defined as clopidogrel, aspirin, and a DOAC, was not associated with improved net clinical outcomes compared to six months triple antithrombotic therapy. Both major bleeding risk and thrombotic risk appeared to be similar with both durations of triple therapy.
PIONEER AF PCI8
Patients who had AF and were undergoing stent placement experienced less bleeding at 1 year with low dose rivaroxaban plus single or dual antiplatelet therapy compared to warfarin plus dual antiplatelet therapy.
Patients with AF who had undergone PCI had a lower risk of bleeding when receiving dual therapy with dabigatran and a P2Y12 inhibitor than those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. The dual therapy regimen was found to be noninferior to triple therapy with regards to the risk of thromboembolic events.
In patients with AF and a recent ACS or PCI, an antithrombotic regimen with apixaban and a P2Y12 inhibitor without aspirin, resulted in less bleeding without significant difference in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.
Prior to the most recent update to the 2014 AHA/ACC/HRS AF Guidelines in 2019, it was recommended that all patients with ACS and AF with a CHA2DS2-VASc score of 2 or greater receive anticoagulation with warfarin unless it is contraindicated.11 Although these older guidelines did discuss minimizing the duration of triple therapy and suggest the option of using oral anticoagulation plus clopidogrel with or without aspirin, there was minimal data to support a formal recommendation. However, more recent studies have shown an improved safety profile with DOACs and dual therapy regimens with regard to bleeding events and similar efficacy at preventing cardioembolic events compared to triple antithrombotic therapy. As a result, dual therapy with an oral anticoagulant and a P2Y12 inhibitor may be more appropriate in some of our patient populations that are at an increased risk of bleeding. The AHA/ACC/HRS AF Guidelines were updated in 2019 to reflect these new findings, and specific recommendations are listed below.
Application in Practice
The incidence of AF in patients with ACS is not uncommon and management often requires the use of both antiplatelet agents and anticoagulants. These medications are vital at reducing the risk of thromboembolic events but put our patients at risk of bleeding. As healthcare professionals, it is important to fully weigh the risks and benefits before initiating triple antithrombotic therapy and to advocate for less aggressive antithrombotic regimens when it is clinically indicated.
By: Brooke Lucas, PharmD and Kelsey Sachtleben, PharmD; PGY1 Pharmacy Residents
Mentor: Emily Buchanan, Pharm.D., BCPS, SSM Health St. Clare Hospital
Take the CE Quiz
Calcium is one of the most abundant cations found in the human body and plays an important role in myocardial function, enzyme activity, neural transmission, coagulation, and other cellular functions. Most calcium is found in the bones with the remainder of calcium found in cells and extracellular fluid.1,2 Hypercalcemia affects approximately one to two percent of the general population, with most of these cases (90%) due to primary hyperparathyroidism and hypercalcemia of malignancy.3 Patients can often tolerate chronic hypercalcemia, but acute hypercalcemia can lead to more severe symptoms and up to a 50% mortality rate for patients with untreated hypercalcemia of malignancy.4
The skeletal tissue of the human body not only provides necessary structural support, but acts as a reservoir from which calcium can be exchanged. Approximately 99% of the total body calcium stores are contained within skeletal tissues. Although only a small fraction of total body calcium exists in extracellular and intracellular fluid, such calcium concentrations are essential for normal action potential propagation, muscle contraction, endocrine and exocrine secretion processes, activation of coagulation factors, and more. Calcium homeostasis is controlled by a set of endocrine regulatory factors discussed further below.5
The three key regulators of ionized calcium concentrations throughout the body are parathyroid hormone (PTH), 1,25-dihydroxy vitamin D3 (calcitriol), and calcitonin. PTH is important in calcium homeostasis as part of hormone signaling and negative feedback loops. When low levels of extracellular calcium are detected, the parathyroid glands begin secreting PTH. PTH works to increase serum calcium by stimulating the release of calcium from skeletal tissue, increasing reabsorption of calcium in the renal tubules, and increasing the absorption of calcium from the gastrointestinal tract with the help of calcitriol released by the kidneys.5 PTH also stimulates phosphate excretion in the kidneys, so low serum phosphate levels may be seen in patients with hypercalcemia secondary to hyperparathyroidism.
Vitamin D is a steroid hormone that is obtained through both diet and activation of vitamin D precursors on the skin via interaction with sunlight. The active form of vitamin D in the body is 1,25-dihydroxy vitamin D3, also known as calcitriol, which is produced by a hydroxylation process in the renal tubules. In the setting of increased serum calcium levels or ingestion of calcium-rich foods, calcitriol is produced in the kidneys and released into circulation. Aside from directly increasing calcium absorption in the gastrointestinal tract, calcitriol also promotes bone resorption, decreases renal excretion of calcium, and stimulates absorption of phosphate from the gastrointestinal tract, thus leading to elevated phosphate levels in patients with calcitriol mediated hypercalcemia.
When serum calcium levels begin to rise above the normal threshold, the hormone calcitonin begins to play a role in maintaining calcium homeostasis. Elevated levels of serum calcium stimulate the release of calcitonin from the parafollicular C cells of the thyroid gland. Calcitonin works opposite of PTH and calcitriol in the regulatory loop to decrease serum calcium levels via inhibition of osteoclast bone resorption and opposing the effects of PTH on the kidneys, promoting calcium excretion.6
Assessing serum calcium concentrations:
The universally excepted normal range for serum calcium concentration is between 8.5 and 10.5 mg/dL. It is important to keep in mind that a value representing the total serum calcium concentration includes both bound and unbound forms of calcium. In the serum, calcium is bound to plasma proteins, predominantly albumin. Knowing that the ionized, or unbound, form of calcium is the physiologically active form of the electrolyte, abnormal serum albumin concentrations may result in the total serum calcium not accurately reflecting the amount of ionized calcium in circulation. To calculate a value that better represents the physiologically active form of calcium in the body, the corrected calcium equation should be used when albumin concentrations are below 4 g/dL (Figure 1).5
Although patients with higher serum calcium concentrations often present with more severe symptoms of hypercalcemia, the staging system for hypercalcemia is based solely on serum lab concentrations as seen below in Table 1. If serum albumin levels are below 4 g/dL, it is important to use the corrected calcium equation prior to staging the hypercalcemia. Staging of hypercalcemia is important for proper selection of appropriate pharmacologic treatment options, which will be discussed later in this article.6
The two most common causes of hypercalcemia are primary hyperparathyroidism and malignancy. Although these two scenarios account for more than 90% of hypercalcemia cases, vitamin D-related causes, medications, other endocrine disorders, and genetic disorders are also possible etiologies. Thorough patient work-up, including past medical history, physical exam, family history, and medication reconciliation is important in the differential diagnosis.6
Signs and symptoms of hypercalcemia are dependent on the severity and the timing of onset. Patients presenting with mild to moderate hypercalcemia are often asymptomatic. This is especially true for patients with drug-induced hypercalcemia or hyperparathyroidism. Signs and symptoms appear more commonly when the calcium concentration is above 13 mg/dL. In patients with hypercalcemia of malignancy, symptoms can present as anorexia, nausea and vomiting, constipation, polyuria, polydipsia, and nocturia. Patients in hypercalcemic crisis may have more severe symptoms including acute renal failure, and other life-threatening symptoms including arrhythmias, tetany, and pancreatitis.5 A common pneumonic utilized to remember the signs and symptoms of hypercalcemia is “Stones, bones, abdominal moans, and psychiatric groans”.6 These and other signs and symptoms are listed in Table 2.
Treatment of Acute Hypercalcemia
When a patient presents with an initial episode of hypercalcemia, it is important to thoroughly review the patient’s past medical history, complete a physical exam, and review both family and medication history for potential etiologies. If a patient presents with asymptomatic, mild hypercalcemia, observation and correcting reversible causes is recommended over pharmacologic treatment. In patients who are symptomatic or present with moderate to severe hypercalcemia, treatment should be initiated with an appropriate first line therapy, including saline hydration or loop diuretics (Figure 2).5
First Line Treatment
Saline hydration should be initiated upon diagnosis of hypercalcemia with a crystalloid, isotonic fluid, including 0.9% sodium chloride solution, commonly referred to as normal saline. Normal saline (NS) expands intravascular volume, increasing natriuresis and decreasing both sodium and calcium reabsorption in the renal tubule. With initiation of NS, one can expect serum calcium levels to decrease within the first 24-48 hours of treatment. Initially, patients should receive 1-2 L of a NS bolus, which should be followed by a maintenance infusion at a rate of 250-300 mL/hour. Maintenance fluid should be continued until serum calcium levels approach the upper end of the normal limit, or until patients have been appropriately fluid resuscitated. While receiving saline hydration, monitoring should include intake and output, daily weight and electrolyte levels, including sodium, potassium, chloride, bicarbonate, and calcium. Patients receiving saline hydration may experience adverse effects including electrolyte imbalances and fluid overload, warranting caution in patients with a history of chronic kidney disease and heart failure.5
Loop diuretics administered intravenously are an additional option for the first line treatment of acute hypercalcemia. These agents inhibit the reabsorption of sodium and chloride in the ascending loop of Henle and the distal renal tubules in the kidneys, interfering with the sodium-potassium-chloride cotransport system. Because of this inhibition, there is an increase in the excretion of water, sodium, chloride, magnesium, and calcium. Loop diuretics often result in a lowering of serum calcium levels within 1 - 2 hours of therapy. Bumetanide and furosemide are both effective at reducing calcium levels (Table 3).5 Although saline hydration is the treatment of choice for acute hypercalcemia, as mentioned above this treatment option may not be the safest for patients with heart failure or reduced renal function. In these special populations, the addition of loop diuretics may be a great option to reduce serum calcium levels while reducing their risk of volume overload with continual NS hydration. Use of IV loop diuretics is most commonly recommended after proper volume depletion has been restored through saline hydration.7 Necessity for IV loop diuretics should be reassessed frequently as serum calcium levels decrease, in order to avoid adverse effects. Patients on loop diuretics should have blood pressure, renal function, intake and output, electrolytes, and weight monitored periodically while receiving therapy. Potential adverse effects associated with therapy include gout flares, increased urination, and electrolyte imbalances.8,9
Figure 2: Acute Hypercalcemia Treatment Algorithm5
Second Line Treatment
There are several additional treatment options for acute hypercalcemia. Alternative options should be considered when additional calcium lowering is needed following first line options, or in patients who are not candidates for either saline hydration or loop diuretics. Calcitonin antagonizes the effects of the parathyroid hormone, directly inhibits osteoclastic bone resorption, and promotes renal excretion of calcium, phosphate, sodium, magnesium, and potassium by decreasing resorption in the renal tubule. Calcitonin’s onset of action is around 2 hours, and the duration is approximately 48 hours.5,10 Calcitonin is started at a dose of 4 international units/kg body weight SQ every 12 hours. Serum calcium and vitamin D levels should be monitored, and potential adverse effects include flushing, nausea, allergic reactions, and respiratory rhinitis.5,10
Bisphosphonates are another alternative option for treatment of hypercalcemia, as they inhibit bone resorption by absorbing to calcium phosphate and preventing it from dissolving in bone. Bisphosphonates also inhibit osteoclast precursors from transforming into functioning osteoclasts. These mechanisms are why bisphosphonate agents fall into the category of antiresorptive therapy.5 Bisphosphonates have a slower onset of action, ranging from 2 - 7 days. Pamidronate and zoledronic acid are intravenous options that may be used for hypercalcemia (Table 4). It is important to note the dosage of zoledronic acid (Zometa®)11,12 for treatment of hypercalcemia, and how it differs from the zoledronic acid (Reclast®)11 recommended dose of 5 mg IV yearly for treatment of osteoporosis. One advantage of pamidronate over zoledronic acid is it can be a single-day therapy option. Serum calcium, potassium, magnesium, phosphate, creatinine, and vitamin D should be monitored periodically while using bisphosphonate therapy, and potential side effects include nausea, vomiting, abdominal pain, myalgia, fatigue, dizziness, dyspnea, bone pain, headache, anemia, urinary tract infections, and osteonecrosis of the jaw.5,11,12,13
In addition, glucocorticoids can offer further calcium lowering effects. Glucocorticoids reduce gastrointestinal absorption of calcium as well as promote calcium excretion in the urine. They have an onset of action ranging from 3 - 5 days. Some glucocorticoid options include prednisone5, dexamethasone14, methylprednisolone15, and hydrocortisone16 (Table 5). Patients taking glucocorticoids should monitor their blood pressure, blood glucose, and weight while on therapy. Potential adverse effects include insomnia, abdominal pain, osteoporosis, immunosuppression, hyperglycemia, hypertension, and psychiatric disturbances.7
Gallium nitrate is not commonly used for treatment of hypercalcemia, but has been historically used in the treatment of symptomatic cancer-related hypercalcemia.5 Dosing of gallium nitrate for treatment of hypercalcemia is typically 100 – 200 mg/m2 IV daily for a total of 5 days.6 Hemodialysis may be indicated in some patients with acute hypercalcemia as a last-line treatment option.5 Hemodialysis may be more commonly considered in patients with renal failure or cardiac comorbidities in whom saline hydration or loop diuretics may not be safe or appropriate options to treat hypercalcemia. Low calcium bath products may be used to treatment of hypercalcemic crisis, and may provide up to one-third clearance of serum calcium concentrations. Calcium free dialysate may lead to hemodynamic instability, and thus is not recommended.18
Treatment of Chronic Hypercalcemia
Patients with non-reversible causes of hypercalcemia may require maintenance therapy to prevent recurrent episodes. The two most common causes of chronic, persistent hypercalcemia are primary hyperparathyroidism (PHPT) and hypercalcemia of malignancy (HCM). PHPT and HCM can be related to over 90% of hypercalcemia cases. The epidemiology of PHPT in the United States ranges from 10-30 cases per 100,000 people, and hypercalcemia associated with cancer occurs in 20-40% of patients during the course of disease.5 Compared to PHPT, HCM is typically associated with more severe clinical symptoms of hypercalcemia and can often be an oncologic emergency. Because of this, HCM is more often diagnosed while patients are hospitalized in contrast to PTPT which is more often diagnosed via laboratory work in the ambulatory care setting. Figure 3 can be useful in the evaluation and treatment of hypercalcemia in patients with or without cancer.
Figure 3: Evaluation and Treatment of Chronic Hypercalcemia19
PTH levels above 20 pg/mL are considered unsuppressed, or high PTH levels in the setting of elevated serum calcium levels. Patients with PHPT are often asymptomatic, and hypercalcemia is usually found incidentally with routine laboratory monitoring. Upon advent of the commonly used electrolyte panel, the diagnosis of PHPT increased. Surgical evaluation should be considered in all, but especially symptomatic patients diagnosed with PHPT. A parathyroidectomy may be indicated in patients less than 50 years old, with a serum calcium level greater than 1 mg/dL above the normal range, bone health risk (osteoporosis or vertebral fracture), or impaired renal function.19
Patients who are not surgical candidates may receive pharmacological management, including bisphosphonates, denosumab, or cinacalcet.19 Cinacalcet is a calcium-sensing receptor agonist that increases the sensitivity of the calcium-sensing receptor on the parathyroid gland, lowering PTH secretion, serum calcium, and serum phosphate levels. Cinacalcet is dosed at 30 mg orally twice daily with a maximum dose of 90 mg three-four times daily. Doses can be adjusted every 2 – 4 weeks. While taking cinacalcet, patients should monitor for potential adverse effects, including hypotension, headache, fatigue, gastrointestinal effects, depression, bone fractures, muscle spasms, weakness, myalgia, and dyspnea.5,20 Information regarding treatment with denosumab can be found in the HCM section below.
Hypercalcemia of Malignancy (HCM)
The two most common causes of HCM are humoral and local bone osteolysis. Although less common, lymphomas may also cause excess calcitriol production, leading to hypercalcemia. If patients present with hypercalcemia, and PHPT has been ruled out, workup for hypercalcemia etiologies in these patients should include identifying a potential underlying malignancy. Presenting symptoms of HCM include the expected gastrointestinal upset, anorexia, polydipsia, polyuria, hypotension, bone pain, fatigue, and confusion, but may also include more severe signs and symptoms such as renal failure, cardiac failure, coma, and even death. The severity of symptomatic presentation correlates to both the degree of hypercalcemia and the rate at which serum calcium has risen.19
After ruling out PHPT as the cause of hypercalcemia, the next important step is assessment of serum PTH-related protein (PTHrP) levels. The secretion of PTHrP from malignant tumor accounts for 80% of HCM cases, and this syndrome is referred to as humoral hypercalcemia of malignancy. The most common tumors associated with this syndrome include squamous cell carcinoma of the lung, head and neck, esophagus, skin, or cervix, as well as carcinomas of the breast, kidney, prostate, or bladder. PTHrP is a protein produced by certain cancer cells, and a serum level > 2.5 pmol/L is significant. As the name implies, PTHrP has effects similar to PTH in some tissues. At the kidneys, PTHrP increases the reabsorption of calcium. By stimulating osteoblasts to secrete RANKL, PTHrP also leads to increased serum calcium levels by stimulating the differentiation of osteoclast precursors into osteoclasts, leading to increased bone resorption. PTHrP assays have become increasingly more accurate and should be checked in all patients with suspected HCM.19
HCM secondary to osteolysis mediated by local tumor cell secretion of osteoclast-activating cytokines is most commonly seen in patients with breast cancer and multiple myeloma. Of note, the mechanism of this form of HCM is not a direct tumor invasion and degradation of bone tissue, but instead caused by cytokines such as IL-1, IL-6, and TNF-alpha acting similarly to PTH to stimulate bone resorption via osteoclasts. Clinically, the differential diagnosis of humoral HCM and bone osteolysis relies upon PTHrP levels, as they will be low in the setting of bone osteolysis. Although associated with less than 1% of HCM, excessive production of calcitriol may lead to hypercalcemia in patients with malignancies, most often seen with lymphomas.19
The primary focus of treating HCM should include treatment of underlying malignancy if able. Patients presenting with acute, symptomatic hypercalcemia should be treated via the algorithm outlined in the acute hypercalcemia section (Figure 2). For treatment and prevention of chronic hypercalcemia, anti-resorptive agents such as intravenous bisphosphonates, denosumab, and calcitonin, as well as glucocorticoids are recommended alongside malignancy treatment. Approved by the FDA in 2014 for treatment of HCM, denosumab is a human monoclonal antibody which binds to RANKL, preventing RANK from binding to osteoclasts. This inhibition leads to decreased osteoclast resorption of bone.19 Denosumab (Xgeva®) is often recommended in HCM that is refractory to bisphosphonate therapy. With an onset of action around 3 days, denosumab should be administered at a dose of 120 mg SQ every 4 weeks, with additional doses administered within the first month of therapy on days 8 and 15.21 It is important to note that this dosing is different than the dosing of denosumab for treatment of osteoporosis, which goes by the separate brand name Prolia®. Adverse effects of denosumab that have been reported include GI upset, peripheral edema, rash, headache, thrombocytopenia, asthenia, back pain, and osteonecrosis of the jaw. Monitoring for denosumab should include renal function, electrolyte levels, signs of infection, hypersensitivity reactions, and routine oral exams.
Calcium plays an important role in many biologic functions throughout the body, and abnormalities in extracellular calcium concentrations can lead to severe symptoms and even death if not addressed. Within the United States, the most common causes of hypercalcemia include primary hyperparathyroidism and malignancy, with up to one-third of patients with cancer experiencing hypercalcemia at some point during the course of disease. Correction of hypercalcemia may include pharmacologic treatment options such as saline hydration, diuretics, bisphosphonates, and steroids. Assessment and correction of underlying etiologies is just as important as initiating pharmacologic treatment to prevent further occurrences of hypercalcemia.
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By: Kacee Verhovec, PharmD; PGY1 Community-Based Pharmacy Resident
Mentor: Michelle Jeon, Pharm.D., BCACP, Walgreens/St. Louis College of Pharmacy
In August 2019, concerns about electronic cigarette use began to grow after the first death associated with the inhaled product was reported.1 Within several months, the death toll reached 68 in February 2020 with nearly 3,000 additional cases leading to hospitalization.2 Unfortunately, safety concerns continued to grow as electronic cigarettes gained popularity in the younger population. How did we get to this point?
The History of Smoking:
In 1492, Christopher Columbus “sailed the ocean blue,” bringing tobacco leaves back to Spain acquired from the Native Americans. Popularity quickly spread throughout Spain and all of Europe. During this time, many believed smoking had curative properties. As a result, tobacco was considered a protected crop and was rationed during times of war. It wasn’t until 1795 when tobacco smoking was linked to a negative health outcome: lip cancer.3 This was followed with a link to lung cancer in 1912. However, this was not reported by the United States (US) Surgeon General until 1964. Shortly after, secondhand smoke was also linked to cancer, leading to age limits on tobacco sales (age 18 beginning in 1992), required health warnings, public smoking bans, and smoking cessation assistance with the nicotine patch first released in 1992.4
In 2003, Chinese pharmacist Hon Lik invented the first electronic cigarette. He was inspired to create this product after witnessing his father die from lung cancer caused by long-term heavy cigarette smoking, in attempts to create a product to help others quit. Shortly after its release, countries around the world began implementing bans on these products, however regulation of these products by the Food and Drug Association (FDA) was implemented nearly 10 years after its release. Age limits for purchasing electronic cigarette products were not implemented until 2018, leading to younger people utilizing these products often due to ease of access.5 Bans of these products did not occur in the US until June 2019 in San Francisco. The first death linked to electronic cigarette use was reported in August 2019.6,7 At the present time, Federal tobacco sales increased to 21years old in December 2019, but questions remain surrounding the future of electronic cigarettes, their regulations, and if they have positive benefit.8
The Pathophysiology of Nicotine Addiction:
The most recent data from the Centers for Disease Control (CDC) indicates that 14% of the US population are smokers, which has been on a decline since 2005. It is estimated that 70% of this population would like to quit and many find the quitting process to be difficult.9
Nicotine is a sympathomimetic that activates the nicotinic receptors in our bodies and most notably, in our brain within the cerebral cortex and limbic system. With this activation, neurotransmitters such as dopamine are released, leading to the rewards pathway and effects of elevated mood and reduced tension, this pathway is shown in Figure 1 above. As nicotine levels decrease after metabolism, the body requires more to continue receptor activation and neurotransmitter release.10 Without more nicotine, the body will go through withdrawal leading to side effects such as cravings, anxiety, and irritability, most frequently leading to additional nicotine intake to relieve these effects. Symptoms typically occur within 1-2 days without nicotine. If nicotine is not replaced, these withdrawal symptoms typically last 2-4 weeks depending on the length of time a person has smoked and the amount a person typically smoked in order to achieve the positive nicotinic effects.11,12
The amount of nicotine required to achieve its desired effects depends on the length of time a person has smoked as nicotinic receptors eventually become desensitized. Desensitization of nicotine receptors requires more nicotine to achieve the positive effects. Utilizing this additional nicotine due to desensitized nicotinic receptors is not associated with the negative side effects typically associated with high amounts.13 Tolerance is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as having one or both of the following: 1. “absence of nausea, dizziness, or other characteristic symptoms despite using substantial amounts of nicotine” or 2. “diminished effect observed with continued use of the same amount of nicotine-containing products.”14 Because of this cycle, smokers tend to have a difficult time with quitting. The CDC estimates that 87% of adult smokers started smoking as adolescents.9 Increased length of smoking history may cause quit attempts to be even more difficult with resulting increased severity of withdrawal symptoms.13 Cigarette smokers have attempted to quit by utilizing electronic cigarettes as many of these products contain nicotine allowing smokers to continue obtaining nicotine without the additional harmful components of cigarettes such as tar.15
A survey of adult electronic cigarette (also known as e-cigarettes) users conducted in the Netherlands and Belgium identified the number one reason for e-cigarette use was to quit smoking. 94% of those surveyed believed electronic cigarettes were “healthier” than smoking cigarettes.15 A following CDC survey reported that the most popular reason for adolescent e-cigarette users initiating use was curiosity.16
Images of a Tanks and mods, rechargeable e-cigarette, and a disposable e-cigarette.
There are several different types of electronic cigarettes available in various designs, but each electronic cigarette has three key components to them: battery, atomizer, and inhaler. The battery allows for the electronic cigarettes to heat up the liquid. The atomizer contains coils attached to the battery that are soaked in the liquid to be vaporized. When these coils are heated, they subsequently heat the liquid atop the coil itself. Heating this liquid results in evaporation. The vapor is then contained within the atomizer allowing this to eventually be inhaled. The inhaler is the mouthpiece used to inhale the vapor contained within the atomizer.17
The liquid added to the device that is to be vaporized (also known as e-liquid) may contain a variety of ingredients.18 The majority of e-liquids contain a base, most frequently containing distilled water, propylene glycol, and vegetable glycerin, a flavoring, and at times nicotine or tetrahydrocannabinol (THC). Not all e-liquid contains nicotine or THC as some are designed to contain only flavoring to attract users.18,19
E-liquids containing nicotine typically equate to one pack of cigarettes per milliliter of liquid (although this may vary depending on the concentration purchased); most bottles of liquid contain around 30 milliliters. One bottle typically costs around $15, making this an attractive option for those attempting to quit for financial reasons.20
Potential Benefits of Electronic Cigarette Use:
At this time, numerous studies have been conducted that suggest the utility of e-cigarettes for smoking cessation. One study published in February 2019 in the United Kingdom, compared the safety and efficacy of e-cigarettes to traditional nicotine replacement therapy for smoking cessation. This study enrolled adult smokers willing to quit in an unblinded randomized controlled trial.21
At 4 weeks, both products led to abstention from cigarettes, but the e-cigarette group showed statistically significant rates of abstention compared to the traditional NRT group, data shown in Figure 3 below. At 52 weeks, both groups continued to show a decline in those continuing to abstain from cigarette smoking, however the e-cigarette group continued to have a higher percentage of patients abstaining from cigarette use. This study also showed improvements in side effects frequently caused by cigarette smoking in the e-cigarette group such as increased phlegm production, cough, wheezing, and dyspnea shown in Figure 4; this was hypothesized to be associated with the higher amount of patients abstaining from cigarette smoking in the e-cigarette group.21
This study also identified that 80% of those in the e-cigarette group who remained abstinent to cigarettes at 52 weeks were still continuing to use the e-cigarette device compared to roughly 9% in the traditional nicotine replacement product group shown in Figure 5. Leading the authors to question if e-cigarettes were a replacement to cigarette smoking rather than a tool for overall complete cessation.21
Risks of E-Cigarette Use:
In the previous study discussed, the e-cigarettes did not come without side effects. Figure 6 lists the most common side effects cited included nausea, throat/mouth irritation, and sleep disturbances; however, throat/mouth irritation was the only side effect cited to be more common in the e-cigarette group compared to the traditional nicotine replacement therapy group.21 Outside of this study, e-cigarettes have also been linked to endothelium changes in vessels, seizures, and physical injuries due to device malfunctions.22,23,24 The vapors produced by these products, including the second-hand smoke, contain harmful organic and inorganic chemicals such as formaldehyde and heavy metals.25 The deaths reported in August 2019 were associated with a peculiar lung injury only present in those with a recent history of e-cigarette use. Since then, the injury has been named “E-cigarette or vaping product use-associated lung injury” or “EVALI.”1,26
EVALI is diagnosed by the following: having symptoms consistent with EVALI, e-cigarette use within the last 90 days, and abnormal chest imaging (most frequently as bilateral ground glass opacities in the lower lobes). Symptoms of EVLAI are not nonspecific. The majority of patients diagnosed show respiratory symptoms such as dyspnea, hypoxemia, cough, chest pain, and hemoptysis. However, 77% of patients also have gastrointestinal complaints such as nausea, vomiting, and diarrhea as well as symptoms such as fatigue, headache, and weight loss. Patients may also show non-specific signs and symptoms such as fever, leukocytosis, and elevated liver function tests. Case reports led to questions of what would be causing such injuries. In the first case series addressing the issue, 89% of those studied reported THC product use within their devices.26,27
THC has become popular over the last few years with more states legalizing its use. A survey attempted to determine what attracted users of THC products within e-cigarettes to use these products instead of smoking cannabis products. The survey revealed using e-cigarettes (or vaping) THC tasted better or cleaner than other routes. Other reasons to vape THC products instead of smoking them included this was easier to conceal as the smell is not as strong, it is convenient, and it produces a stronger high than other routes.28
Some patients presenting with EVALI who reveale a history of vaping THC products underwent bronchi alveolar lavage (BAL) revealing a non-infectious disease, non-specific inflammation, and increased levels of lipid-laden alveolar macrophages.26 Alveolar macrophages act as the first line of defense for the lungs, clearing foreign bodies including external lipids. While it is normal to have a small amount of lipid-laden macrophages on the results of a BAL, these patients showed an excessive amount. This finding led to further testing of vaped THC products.29 It was identified that 94% of these products contained vitamin E acetate, a lipid containing additive.26 While the most popular THC-containing e-liquids did not report such additives, many did display warnings of fake products being sold.30,31 THC solutions have a naturally high viscosity, especially in comparison to nicotine solutions. Vitamin E acetate has a viscosity similar to THC and is often used as a thickening agent in fake products to deceive consumers.32
Vitamin E acetate is a problem in the lungs for two main reasons. First, vitamin E acetate has shown to penetrate lung surfactants, leading to a loss of surface tension. This eventually may result in damaged lung tissue, and increased risk of a collapsed lung. Another mechanism in which vitamin E acetate damages the lungs is when heated, vitamin E acetate breaks down into 30-ketene, a known lung irritant. This metabolite can cause inflammation in the lungs and eventual damage to the tissue.32 When mice were exposed to vitamin E acetate aerosols, the BAL performed showed very similar results to humans including this increase in lipid-laden alveolar macrophages.33
It is important to note that although there have been some potential benefits with utilizing these products, in particular for smoking cessation, there are risks that we currently know and risks we may not. Centuries passed before negative health effects were definitively associated with cigarette smoking, while e-cigarettes have only been around since 2006.5
Rules and Regulations of Electronic Cigarettes:
FDA regulations on e-cigarette products did not occur until 2016, about ten years after its introduction to the United States. The federal minimum age limit for purchase was set in 2018 at 18 years old. 2016 FDA regulations cited that any product on the market prior to February 15, 2007 was exempt from FDA regulations and products on the market after that date was considered a new product. New products must be authorized by the FDA by September 9, 2020 to continue to be produced and sold.34 Therefore, there may still be products currently being sold that have not been approved by the FDA for sale.35 This approval process requires manufacturers to provide paperwork reporting product labeling, ingredients, advertisements, and warning label display.34
On December 20, 2019, the Federal Food, Drug, and Cosmetic Act was amended to increase the federal minimum age limit for purchase of tobacco products to 21, increasing the age from the previous limit of 18 years old.36 E-cigarettes and e-liquid are currently regulated as tobacco products, only if they contain nicotine.34 In 2019, 27% of high school students reported using e-cigarettes.37 To deter this age group from these products, several legislations at the federal and state level have been introduced, including a call for increased taxes on sale of these e-cigarettes and for banning of flavored e-liquids. Currently, Missouri has not implemented either of these.38
CDC Recommendations for E-Cigarette Use:
The CDC recognizes the potential risks and benefits associated with e-cigarette use and have recommended those not currently using combustible or non-combustible products such as e-cigarettes should not start using them. Pregnant women, adolescents, and young adults should never partake in vaping any products. However, those currently using e-cigarettes specifically for smoking cessation should not go back to using combustible products, should not utilize both e-cigarettes and combustible products at the same time, and should ensure e-liquids or devices come from a reputable source such as in-person e-cigarette or vape shops rather than online dealers, family, or friends. Other FDA-approved smoking cessation products would be preferred. The CDC also recommends against the use of THC products within e-cigarettes, especially those containing vitamin E acetate.39 The World Health Organization addresses these concerns similarly, however they address the lack of data behind e-cigarettes for smoking cessation and recommends currently known effective interventions for smoking cessation instead.40
The American Cancer Society agrees with the recommendations provided by the CDC however they also explicitly state being against the use of e-cigarettes for smoking cessation until a product is approved by the FDA to be used for this purpose alone.41 The American Lung Association states they do not support the use of e-cigarettes even for smoking cessation. They believe there should be increased regulations in regards to e-cigarettes.42 In addition, the American Medical Association agrees with these recommendations, calling for a total ban on e-cigarette products not meeting FDA approval as cessation tools and currently there are no such products available on the US market.43
The current recommendations for use from numerous health organizations all agree people should not start using e-cigarettes leisurely and agree there are still unknowns associated with the devices’ safety, however recommendations regarding cigarette smoking cessation is still widely controversial. It is important for pharmacists to provide as much education to patients regarding the use of e-cigarettes so users are fully informed of their widely unknown risks and possible benefits.
By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
Every time we turn on the TV or Twitter feed, we face a barrage of facts and opinions about rules. From masks to sports to school policy to social justice, it is impossible to ignore the fact that rules and rule-makers play a huge role in our everyday lives. It is also an interesting case study in the interplay among the rules at the federal, state, and local level, as well as how those rules play out in the real world of businesses and organizations and the family. When done well, rules level the playing field and keep us safe. While there are certainly huge differences in opinions about the definition of ‘good rules,’ everyone can agree that more input from more voices is the best way to create them. This is especially true when the data is conflicting and the basic understanding of the situation changes frequently. This type of scenario calls for leaders of bold vision who also ask questions and listen. Put simply, regulation in uncertain times requires participation. As MSHP members, we can participate by staying knowledgeable and getting involved.
Subscribe to newsletters, such as the Board of Pharmacy, MSHP, and ASHP. For example, our Missouri Board of Pharmacy has been very active as they have provided flexibility to Missouri pharmacies to deal with the pandemic response, and all of the information you need to know has been posted on the website and sent out via newsletters. You can subscribe to the ASHP Daily Briefing as well as Advocacy Updates and other options through your account NewsLink settings. You can also participate in the conversation on ASHP Connect. This MSHP newsletter is always informative, and MSHP is expanding our use of social media platforms to share information. Joint Commission, NABP, and USP also provide useful information. Read through the Pharmacy Practice Guide and the Department of Health hospital pharmacy rules. Schedule time on your work calendar or your personal calendar to catch up on current events in pharmacy and actually read those articles that are sitting in the “Read Me” folder. A small investment of time, consistently applied over weeks and months, will compound into a solid foundation of understanding.
Participate at your workplace as they work out the best plan for providing excellent pharmaceutical care in the ever-changing COVID landscape. Provide your input and your questions to the discussions about how to ensure that care, respect and opportunity is experienced by all patients and teammates, regardless of race. Join a committee or attend a live or virtual event to get involved with MSHP, with your regional chapter of MSHP, or with ASHP. Find out who your legislators are (link), and contact them. Let them know that pharmacists play an important role for our patients, and if we are given provider status we could do even more. It is an election year, so get educated and vote.
Uncertain times call for participation at all levels. As pharmacists, we have a responsibility to stay knowledgeable and get involved to ensure that our patients get the care that they need.
By: Nathan Hanson, PharmD, MS, BCPS
Have you ever wondered what the public policy committee does? As our previous article explained, you can learn about pharmacy by comparing it to sports, and in both settings, rules matter. (That has been taken to an extreme lately, because laws and rules have kept elite athletes on the sidelines!) The Public Policy Committee keeps an eye on 3 basic levels of pharmacy rules: Legislative, regulatory, and association. It has been a crazy couple months in healthcare rules, so we have put together just a few updates in all 3 spheres. Remember, MSHP matters. Collaboration is a priority. Things are changing. Stay engaged!
Legislative: Elected officials and votes
The Missouri legislative session wrapped up, after being significantly disrupted by COVID. Many of the legislative priorities were put on the backburner (think 2021), and a statewide Prescription Drug Monitoring Program was again voted down. However, a helpful proposal was passed that will make it safer for our patients to receive specialized compounded medications. When it has been signed by the governor MSHP will provide more information about how to implement this change. This is a patient safety improvement, and it was a wonderful example of MSHP working together with the Missouri Pharmacy Association and the Missouri Hospital Association to make a positive impact. We truly appreciate their leadership on this issue!
Regulatory: Government employees, inspectors, and boards
The Missouri Board of Pharmacy did an amazing job of responding to the public health emergency. They held multiple meetings and worked tirelessly over the past 3 months to ensure that they had done everything they could do to remove regulatory barriers that might get in the way of providing safe care to patients during the COVID emergency. Thankfully, many of the worst case scenarios did not materialize, but Missouri made a strong effort to be ready. The 2008 USP 797 standards will continue to be in effect, as the revisions go through the committee again. The FDA has finalized a document outlining clear regulatory cooperation with the state boards for interstate compounding. Each state board will review the document to determine if it meets the needs of their state.
Associations: Groups of thought leaders, providing best practices and direction for the profession
The 2020 ASHP House of Delegates has approved a slate of professional policies (link). These are designed to clearly explain the wishes and priorities of the 55,000 ASHP members. They are developed and approved with input from elected members from each state, including member of MSHP. MSHP Board of Directors approved guidance for safe implementation of a technician product verification program within the hospital setting. This guidance document was put to the membership for a vote and was passed. Stay tuned for more information.
By: Lauren Jacobsmeyer, PharmD
Sepsis is a life-threatening illness characterized by a dysregulation in host response to infection characterized by circulatory, cellular, and metabolic abnormalitites.1 Sepsis and septic shock affect millions around the world each year. Sepsis is a primary cause of mortality in Intensive Care Units (ICUs), and its incidence has doubled in the last 10 years.2 Greater than 50% of hospital deaths are due to sepsis with the mortality rate increasing as disease severity increases.3 Mortality rates are reported to range from 10 – 20% in patients diagnosed with sepsis and 40 – 80% in patients diagnosed with septic shock.3,4 In 2013, over $24 billion was spent in the United States on sepsis related hospital expenses, making sepsis the most costly inpatient disease state to manage.3 Based on the high rates of morbidity and mortality in combination with the large financial burden on the health care system, researchers are focused on identifying interventions that reduce sepsis related mortality. One of the most recent interventions of focus is the vitamin C, hydrocortisone, and thiamine three-drug combination.
Surviving Sepsis Campaign Guidelines1
In 2016, the Society of Critical Care Medicine released the Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock. The recommendations put forth in these guidelines were produced by a committee of 55 international experts representing 25 international organizations and serve as a current guideline for the provision of sepsis related care. These guidelines discuss interventions that have a proven mortality benefit in sepsis, including appropriate antimicrobial therapy and source control. They also explore various recommendations including interventions related to resuscitation techniques and adjunctive therapy for continued hemodynamic support including the use of corticosteroids. The guidelines recommend against the use of intravenous hydrocortisone if hemodynamic stability is restored with adequate fluid administration and vasopressor therapy. However, if adequate fluid resuscitation and vasopressor therapy are not able to restore hemodynamic stability, the guidelines suggest the use of intravenous hydrocortisone at a dose of 200 mg per day. This recommendation is classified as a weak recommendation based on a low quality of evidence. Currently, the guidelines make no recommendation regarding the use of the three-drug combination of vitamin C, hydrocortisone, and thiamine.
Steroids in Septic Shock
Steroid use in the setting of sepsis still remains controversial after the publication of the Surviving Sepsis Campaign Guidelines. It is important to note the weak recommendation with low quality evidence to use corticosteroids in the setting of refractory septic shock made by the Surviving Sepsis Campaign did not include evidence from two clinical trials due to the timing of publication. The two large clinical trials focusing on the use of corticosteroids in septic shock published following the publication of these guidelines include the ADRENAL5 and APROCCHSS6 trial.
Adjunctive Glucocorticoid Therapy in Patients with Septic Shock, or the ADRENAL trial, was published in March of 2018. In this multicenter, double-blind, parallel group, randomized controlled trial, researchers sought to determine whether hydrocortisone resulted in lower mortality than placebo amongst patients with septic shock. A total of 3658 patients were included in this trial with 1832 patients randomized to the hydrocortisone group and 1826 patients randomized to the placebo group. Patients in the hydrocortisone group received hydrocortisone 200 mg intravenously (IV) daily by continuous intravenous infusion (CIVI) over a period of 24 hours for seven days or until ICU discharge or death, whichever occurred first. All other aspects of sepsis related care were conducted at the discretion of the treating clinician. Baseline characteristics were well matched between the hydrocortisone group and placebo group. Patients mean age (±SD) was 62.3±14.9 years in the hydrocortisone group and 62.7±15.2 in the placebo group; the median APACHE II scores (IQR) were 24 (19 – 29) in the hydrocortisone group and 23 (18 – 29) in the placebo group. Patients with an APACHE II score ≥25 in the hydrocortisone group versus the placebo group was 45.9% versus 43.1%. Examining sepsis therapy at baseline, 99.5% of patients in the hydrocortisone group and 99.7% of patients in the placebo group were receiving an inotrope and/or vasopressor at the time of randomization and 98.3% and 98.1% of patients, respectively, were receiving antimicrobial agents at the time of randomization. Time from ICU admission to randomization in hours for the hydrocortisone group was 26.1±70.7 and for the placebo group 28.9±72.8 and time of shock onset to randomization was 20.9±91.9 versus 21.2±83.4, respectively. No difference was found in the primary outcome, 90-day all-cause mortality, between the hydrocortisone group and the placebo group, 27.9% versus 28.8% (OR 0.95; 95% CI 0.82 – 1.10; p = 0.50). Additionally, a statistically significant difference was not found in 28-day all-cause mortality between the hydrocortisone group and the placebo group, 22.3% vs. 24.3% (OR 0.89; 95% CI 0.76 – 1.03). One of the secondary outcomes demonstrated patients who received hydrocortisone had a quicker time to shock reversal with the median days to shock reversal (IQR) in the hydrocortisone group being 3 days (2-5) versus 4 days (2-9) in the placebo group (HR 1.32; 95% CI 1.23 – 1.41; p <0.001). Patients in the hydrocortisone group also had a shorter median (IQR) time to ICU discharge than the placebo group, 10 days (5 – 30) versus 12 days (6 – 42) (HR 1.14; 95% CI 1.06 – 1.23; p <0.001). Adverse effects were reported based on clinical judgment and were not an outcome measure of this study. Authors’ concluded among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day all-cause mortality than placebo.5
Hydrocortisone plus Fludrocortisone for Adults with Septic Shock, or the APROCCHSS trial, was also published in March of 2018. This was a multicenter, double-blind, 2-by-2 factorial design, randomized trial. Researchers sought to determine in adult patients admitted to the ICU if low dose hydrocortisone plus fludrocortisone for 7 days affects 90-day all-cause mortality. In total, 1241 patients were included, 614 patients in the hydrocortisone-plus-fludrocortisone group and 627 patients in the placebo group. Patients in the hydrocortisone-plus-fludrocortisone group received hydrocortisone 50 mg IV every 6 hours and fludrocortisone 50 mcg per nasogastric tube daily for seven days without taper and patients in the placebo group received matched placebo. Baseline characteristics were well matched between groups. The mean age (±SD) in years was 66±14 in the hydrocortisone-plus-fludrocortisone group versus 66±15 in the placebo group, and the SOFA score (±SD) was 12±3 in the hydrocortisone-plus-fludrocortisone group and 11±3 in the placebo group. Looking at sepsis related care, 96.9% of patients in the hydrocortisone-plus-fludrocortisone group received appropriate antimicrobial therapy versus 96.2% in the placebo group, and 86.9% of patients in the hydrocortisone-plus-fludrocortisone group were receiving norepinephrine at the time of randomization compared to 88.0% of patients in the placebo group. A statistically significant difference was found in the primary outcome, 90-day all-cause mortality with a mortality rate of 43.0% in the hydrocortisone-plus-fludrocortisone group versus 49.1% in the placebo group (RR 0.88; 95% CI 0.78 – 0.99; p = 0.03). Difference was also seen in additional mortality outcomes with the mortality rate being significantly lower in the hydrocortisone-plus-fludrocortisone group than the placebo group at ICU discharge (35.4% vs. 41.0%; p = 0.04), hospital discharge (39.0% vs. 45.3%; p = 0.02), and day 180 (46.6% vs. 52.5%; p = 0.04). However, no significant difference was seen in 28-day mortality rate between the hydrocortisone-plus-fludrocortisone group versus the placebo group (33.7% vs. 38.9%; p = 0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than the placebo group (17 ±11 vs. 15 ±11 days; p <0.001). There were no statistically significant differences in serious adverse events, gastroduodenal bleeding, rate of superinfection, new sepsis, or new septic shock between groups. A statistically significant difference was seen between the hydrocortisone-plus-fludrocortisone group versus control group in ≥1 episode of blood glucose levels ≥150 mg/dL by day 7 (89.1% vs. 83.1%; p = 0.002). The mean (±SD) number of days with ≥1 episode of blood glucose levels ≥150 mg/dL by day 7 was 4.3±2.5 in the hydrocortisone-plus-fludrocortisone group versus 3.4±2.5 in the placebo group (p <0.001). Authors’ concluded that in patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo.6
The ADRENAL and APROCCHSS trials demonstrate different outcomes regarding the mortality benefit of corticosteroids in patients with refractory septic shock, but both demonstrate quicker time to shock resolution with corticosteroid use. The use of corticosteroids in the setting of refractory septic shock remains controversial, but it is a standard of care at many institutions due to the shorter resolution of shock symptoms and arguable mortality benefit. In an effort to develop an intervention to reduce sepsis related mortality, researchers have begun to investigate the administration of corticosteroids in combination with vitamin C and thiamine.
Vitamin C, Hydrocortisone, and Thiamine Combination Therapy
Vitamin C, hydrocortisone, and thiamine have been an interest of clinical research based on the pathophysiology supporting the three-drug combination, the minimal adverse effects associated with the medications, and the theoretical low-cost of the intervention. In the setting of sepsis, organ dysfunction can be attributed to a decrease in systemic vascular resistance resulting in decreased organ perfusion and thus decreased oxygen delivery. Organ dysfunction also occurs in sepsis in the absence of decreased organ perfusion. A variety of mechanisms have been proposed to cause organ dysfunction including mitochondrial dysfunction, a direct effect of the immune response to infection, microvascular abnormalities, and endothelial dysfunction. Traditional sepsis management including resuscitation with fluids and administration of vasopressors, focus on improving oxygen delivery to end organs. Vitamin C, hydrocortisone, and thiamine are theorized to provide overlapping and synergistic actions to target the non-oxygen delivery-dependent mechanisms of organ dysfunction.7,8
Hydrocortisone has long been theorized to benefit patients with septic shock because it decreases inflammation by suppression and migration of white blood cells and provides reversal of increased capillary permeability. Using stress dose steroids also supplements the adrenal dysfunction common in septic patients.7,8
In the setting of sepsis, reactive oxygen species (ROS) are produced in neutrophils. ROS invade and kill microorganisms but can also damage healthy host cells. Vitamin C serves as a potent antioxidant that decreases the damage caused to host cells due to ROS and protects many microvascular cellular functions that may be impaired during sepsis. Microvascular functions that vitamin C has been proven to protect in animal models include preserving tight junction, decreasing the microvascular permeability barrier, preserving capillary blood flow, and increasing arteriolar responsiveness to vasoconstrictors. Vitamin C has a relatively minimal side effect profile but most notably has been reported to cause hyperoxaluria, an excessive excretion of oxalate in the urine.7-10
The rationale for use of thiamine in the three-drug cocktail is two-fold. Thiamine works to prevent the formation of oxalate crystals in the kidneys, and it also treats a potential thiamine deficiency seen in septic patients. Thiamine plays an essential role in mitochondrial metabolism at the molecular level. Thiamine deficiency leads to impaired glucose metabolism, oxidative stress, glutamate excitotoxity, and inflammation. These metabolic derangements caused by thiamine deficiency can result in cell dysfunction and death. By providing thiamine, theoretically cell dysfunction and death can be prevented. Thiamine also provides a necessary cofactor for the metabolism of glyoxylate to oxalate, to prevent the development of hyperoxaluria in the setting of high-dose vitamin C administration. This prevents the development of renal impairment that is possible in the setting of hyperoxaluria.7,8,11
The three-drug combination together is theorized to work by hydrocortisone and vitamin C acting synergistically on multiple sites of the inflammatory cascade. Additionally, hydrocortisone facilitates the uptake of vitamin C into the cell by increasing the expression of sodium dependent transporters. Inside the cell, vitamin C is thought to restore the efficacy of glucocorticoid receptors providing the means for corticosteroids to work to prevent microvascular complications.7 Thiamine is used in the three-drug combination to prevent the development of hyperoxaluria by providing the necessary cofactor for the conversion of glyoxylate.8 The proposed synergy of these medications and the potential mortality benefit of this three-drug cocktail has been studied in limited clinical trials.
Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock12
The first study to examine the three-drug combination of vitamin C, hydrocortisone, and thiamine was published by Paul Marik and colleagues in 2017. This study was a single-center, retrospective, before-after clinical study that used historical controls to determine if intravenous vitamin C, hydrocortisone, and thiamine in addition to standard sepsis treatment, improve mortality in ICU patients with severe sepsis and septic shock, compared with standard treatment alone. In this before-after trial, the authors compared the outcomes and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a seven-month period. The control group was treated in the preceding seven months. Patients in the treatment group received vitamin C 1.5 g IV every 6 hours for four days or until ICU discharge, hydrocortisone 50 mg IV every 6 hours for 7 days or until ICU discharge followed by a taper over 3 days, and thiamine 200 mg IV every 12 hours for four days or until ICU discharge. All study medications were initiated within 24 hours of ICU admission. Sepsis related care was similar except for the administration of the vitamin C, hydrocortisone, and thiamine combination to the treatment group. Researchers noted there were no known significant changes to ICU protocols during the study period. Patients in the control group were allowed to receive hydrocortisone 50 mg IV every 6 hours at the discretion of the treating physician. Forty-seven patients were included in the treatment group as well as the control group. Baseline characteristics were well matched between groups. Mean (±SD) age in the treatment group was 58±14.1 years versus 62.2±14.3 years in the control group; both 46% of patients in the treatment and control group received vasopressor therapy; the day 1 SOFA score (mean ±SD) of patients in the treatment group was 8.3±2.8 versus 8.7±3.7 in the control group; and the APACHE II (mean ±SD) in the treatment group was 22.1±6.3 versus 22.6±5.7 in the control group.
A statistically significant difference was seen in the primary outcome, hospital mortality in the treatment group versus the control group (8.5% vs. 40.4%; p <0.001). Researchers also found statistically significant differences between the treatment group and control group for the secondary outcomes of duration of vasopressors and the change in SOFA score at 72 hours. The duration of vasopressors (mean ±SD) in hours in the treatment group was 18.3±9.8 versus 54.9±28.4 in the control group (p <0.001). The change in SOFA score at 72 hours was 4.8±2.4 in the treatment group versus 0.9±2.7 in the control group (p <0.001). Study researchers note 28/47 (59.6%) patients in the control group were treated with hydrocortisone since this was included in standard sepsis treatment.
The authors concluded the early use of intravenous vitamin C, moderate dose hydrocortisone, and thiamine may prove to be effective in preventing progressive organ dysfunction and reducing mortality in patients with severe sepsis and septic shock. However, authors discuss additional studies are required to confirm the preliminary findings of this study which was the first study to evaluate the vitamin C, hydrocortisone, and thiamine combination.
VITAMINS Randomized Clinical Trial13
Due to the study design and small sample size of the clinical trial conducted by Paul Marik and colleagues, it remained unclear whether vitamin C, hydrocortisone, and thiamine in combination provide a mortality benefit in septic shock patients. Investigators from the VITAMINS trial sought to determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.
This multicenter, open-label, randomized clinical trial was conducted in ten ICUs in Australia, New Zealand, and Brazil. Patients admitted to the ICU and with a primary diagnosis of septic shock based on the SEPSIS-3 definition were included in this trial. Patients in the trial were randomly assigned to the intervention group or the control group. The patients in the intervention group received vitamin C 1.5 g IV every 6 hours, hydrocortisone 50 mg IV every 6 hours and thiamine 200 mg IV every 12 hours, and patients in the control group received solely hydrocortisone 50 mg IV every 6 hours. The study intervention was continued until cessation of vasopressor administration or when any of the pre-defined stopping criteria were met. The predefined stopping criteria included shock resolution defined as when all vasopressors were discontinued for four consecutive hours in the presence of a mean arterial pressure (MAP) > 65 mmHg or achievement of MAP set by the treating clinician; 10 days of vitamin C and thiamine had been administered in the intervention group; 7 days of hydrocortisone had been delivered to the control group; death; discharge from the ICU; contraindications to any of the study drugs had arisen; or serious adverse events suspected to be related to a study medication developed. The primary outcome for this study was time alive and free of vasopressors at day 7 (168 hours) after randomization. This was defined as time, censored at 7 days, that a patient was both alive and had not received vasopressors for at least 4 hours. If a patient died while receiving vasopressor therapy following the initial episode of septic shock, the patient was assigned zero hours for the outcome. Additionally, if a patient was weaned from all vasopressors for 4 consecutive hours, then all of the remaining time through day 7 was treated as a success, even if the patient died or had vasopressors restarted after weaning within the 7-day period.
A total of 216 patients were included in this study, 109 patients in the intervention group and 107 in the control group. Baseline characteristics were similar between the two groups, however, baseline characteristics in this study were not compared to determine if there was a statistically significant difference at baseline between the intervention and control group. The mean (±SD) age of the intervention group was 61.9±15.9 years versus 61.6±13.9 years in the control group. The mean (±SD) APACHE III score in the intervention group was 77.4±29.7 versus 83.3±28.8 in the control group and the mean (±SD) SOFA score at admission was 8.6±2.7 in the intervention group and 8.4±2.7 in the control group. Patients could receive hydrocortisone prior to randomization with 42.1% of patients in the intervention group and 37.5% of patients in the control group receiving hydrocortisone prior to randomization. Vitamin C administration was not allowed in the control group since it was not a standard of care in study ICUs. Patients in the control group were allowed to receive thiamine at the discretion of the treating ICU clinician with 7.7% of patients in this group receiving thiamine. Median time from ICU admission to randomization in the intervention group was 13.7 hours (7.1 – 19.3) and in the control group 11.4 hours (5.5 – 17.8).
Researchers did not find a statistically significant difference in the primary outcome measurement of time alive and free of vasopressors up to day 7 between the intervention and control group. Median time alive and free of vasopressors up to day seven was 122.1 hours [76.3 – 145.4] in the intervention group versus 124.6 hours [82.1 – 147.0] in the control group (median of all paired differences between group, -0.6 hours (95% CI -8.3-7.2; p = 0.83). The only secondary outcome that demonstrated a statistically significance difference was the change in SOFA score at day three. Change in SOFA score at day 3 was significantly greater in the intervention group than the control group, with the median change in SOFA score -2 [-4-0] versus -1 (-3-0) (difference-1.0, 95% CI -1.9 to -0.1; p = 0.02). No significant between-group difference in 28-day all-cause mortality, 90-day all-cause mortality, ICU mortality, or hospital mortality were found. Additionally, no statistically significant between-group difference in 28-day cumulative vasopressor-free days, 28-day cumulative mechanical ventilation-free days, or 28-day cumulative renal replacement therapy-free days. Adverse events were reported based on clinician judgment and not a prespecified outcome. Two patients in the intervention group and one patient in the control group were noted to have adverse events.
Authors concluded in patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. They discuss these findings suggest treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to more rapid resolution of septic shock compared with intravenous hydrocortisone alone.
Comparing the Data12,13
Compared to the study conducted by Paul Marik and colleagues, the VITAMINS trial was the first randomized clinical trial examining the effect of the combination of vitamin C, thiamine, and hydrocortisone on sepsis. The VITAMINS trial included a larger number of patients than the study by Marik and colleagues and randomized patients to the intervention group or control group. However, in the VITAMINS trial researchers were not blinded to the study intervention. Even without investigator blinding, the design of the VITAMINS trial overcame many of the methodologic limitations of the single-center before-after study design used by Marik and colleagues.
Patients in the intervention group of the VITAMINS trial received the same dose of vitamin C, hydrocortisone, and thiamine that were administered to the patients in the study by Marik and colleagues. However, the treatment duration was longer in the VITAMINS trial providing a longer time period to see the effect of the intervention. Patients in the control group in the VITAMINS trial received hydrocortisone. The administration of hydrocortisone to patients in the control group in the trial by Marik and colleagues was not required, but 59.6% of patients in the control group received hydrocortisone based on discretion of the treating physician. Marik and colleagues did not conduct a subgroup analysis comparing the patients in the control group who received hydrocortisone to the patients in the intervention group.
A major limitation of both studies is the reporting of sepsis related cares. From previous data we know that appropriate antimicrobials and source control provide a mortality benefit in sepsis. The time to appropriate antimicrobials and the determination of appropriate antimicrobial administration was not reported in either of these studies. The amount of fluid resuscitation was also not quantified leading the reader to assume patients received appropriate resuscitation prior to the initiation of vitamin C, hydrocortisone, and thiamine. Without the knowledge regarding the provision of other sepsis related cares, it is hard to determine if the mortality benefit or lack of mortality benefit was due to the three-drug combination or other sepsis related cares.
Marik and colleagues found a statistically significant mortality benefit in the treatment group as well as quicker resolution in shock symptoms. These results were not repeated in the VITAMINS trial, where researchers found no significant difference in time alive and free of vasopressors at day 7. No difference was seen in any of the secondary mortality outcomes in the VITAMINS trial. Adverse effects were not a pre-specified outcome in either of these clinical trials. The results from these two trials are difficult to compare given the unknown sepsis related care provided to patients in each study. Based on current data, the mortality benefit from vitamin C, hydrocortisone, and thiamine remains questionable. The true adverse effects from this three-drug combination also remain unknown.
On the Horizon: VICTAS Clinical Trial14
To further examine the use of vitamin C, hydrocortisone, and thiamine in septic shock patients the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) trial is currently being conducted. This is a double-blind, placebo-controlled, adaptive randomized clinical trial designed to investigate the efficacy of the combined use of vitamin C, thiamine, and corticosteroids versus placebo in patients with sepsis. The objective of this study is to determine the efficacy of the vitamin C, hydrocortisone, and thiamine combination in reducing mortality and improving organ function in septic patients. A total of 501 patients have been included in this clinical trial with patients in the treatment group receiving vitamin C 1.5 g IV every 6 hours, hydrocortisone 50 mg IV every 6 hours, and thiamine 100 mg IV every 6 hours. The primary outcome looks at vasopressor and ventilator-free days at day 30 after randomization, calculated by recording all start and stop days for these measures. Secondary outcomes include 30-day all-cause mortality, ICU mortality, 180-day all-cause mortality, length of hospital stay and length of ICU stay. Per ClinicalTrials.gov, the VICTAS trial was completed in January 2020.
Even with new data regarding the use of a vitamin C, hydrocortisone, and thiamine three-drug combination in patients with septic shock, the actual mortality benefit of the intervention remains unknown. While the use of this combination is feasible in patients with septic shock, many questions regarding the three-drug combination remain unanswered including the optimal time of initiation, optimal medication doses, optimal treatment duration, and potential adverse effects. Additionally, questions remain if the benefit comes from the combination of vitamin C, hydrocortisone, and thiamine or if the benefit is due to a single agent. Further research is needed to determine the benefit of the vitamin C, hydrocortisone, and thiamine combination and answer the additional questions regarding the therapy. Based on limited data, the vitamin C, hydrocortisone, and thiamine combination has not shown negative clinical effects, but its place in sepsis care remains heavily debated causing inconsistency in clinical practice. To ensure the reduction of mortality in patients with sepsis, clinicians should first ensure all intervention proven to decrease mortality are implemented, including appropriate antimicrobial therapy and infection source control, prior to the initiation of the vitamin C, hydrocortisone, thiamine combination.
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By: Brandon Reynolds, PharmD, BCPS
Methicillin-resistant Staphylococcus aureus (MRSA) is found on the skin, axilla, groin, and nares, with the nares being the most common site of colonization.1 According to the Centers for Disease Control and Prevention (CDC) approximately 33% of patients have Staphylococcus aureus nasal colonization, while 2% harbor MRSA.2 Between methicillin-susceptible and MRSA strains, MRSA accounts for the majority of Staphylococcus aureus infections in intensive care units (ICUs).1 In one study published in 2010, patients with Staphylococcus aureus nasal colonization of either MRSA or methicillin-susceptible strains had between a two and four times higher risk of developing an ICU-acquired Staphylococcus aureus infection.3 In another study conducted by Eiff and colleagues, 85.7% of those nasally colonized with MRSA who later developed MRSA bacteremia had an identical strain of MRSA to that colonized in their nares.4 The association between Staphylococcus aureus nasal colonization and pathogenic infection provides a possible antimicrobial stewardship tool to improve the use of anti-infective drug therapy.
Medication therapy used in the treatment of MRSA infections typically includes vancomycin or linezolid based on the site of infection and patient-specific factors, with vancomycin being a commonly ordered first-line agent in several of the currently published guidelines by the Infectious Diseases Society of America (IDSA).5-11 Vancomycin therapy poses significant risks including nephrotoxicity, ototoxicity, and the development of antimicrobial resistance.12-13 Given these risks efforts to decrease the empiric use of vancomycin when it is not needed have become an important consideration for antimicrobial stewardship programs.13 Using MRSA nasal swabs to de-escalate antibiotics active against methicillin-resistant Staphylococcus aureus has gained traction with community acquired pneumonia,6 but the use of these swabs for other sites of infection with a risk of MRSA necessitates further evaluation. This review analyzes the evidence available for MRSA swabs in some of the disease states where anti-infective therapy active against MRSA is commonly used, including pneumonia, bacteremia, osteomyelitis, and skin and soft tissue infections.
In 2019, the community acquired pneumonia (CAP) guidelines published by the IDSA and the American Thoracic Society (ATS) were updated with a more pronounced stance on the use of MRSA nasal swabs than previous guideline iterations.6 The use of MRSA nasal swabs with polymerase chain reaction (PCR) evaluation is now recommended for some patients prior to starting antibiotics active against MRSA, and is also recommended as a tool to de-escalate MRSA coverage in patients already started on therapy.6 Regarding hospital-acquired and ventilator-associated pneumonia (HAP and VAP), the most recent guideline updates were published by IDSA and ATS in 2014.14 In this iteration, the use of MRSA nasal swabs to de-escalate or hold antibiotic therapy active against MRSA is limited, potentially due to a lack of available literature at the time of publication.
A meta-analysis of the current literature regarding the utility of MRSA nasal screens to rule out MRSA pneumonia was conducted in 2018 by Parente and colleagues.15 In this study, 22 trials were included for analysis, representing a total of 5163 patients. The results of this study are shown in table 1.
Table 1. MRSA nasal swab meta-analysis for pneumonia by Parente et al.
In this analysis by Parente and colleagues, MRSA nasal PCR tests were used in 12/22 studies. PCR-based methods had a sensitivity of 78% and a specificity of 92%. Culture-based methods had a sensitivity of 58% and a specificity of 88%. Negative predictive values were over 94% for all pneumonia types, including HAP and VAP. The high negative predictive values suggest a high likelihood that the infecting organism is not MRSA if none is detected in the nares, which allows the clinician to safely de-escalate therapy.
Findings such as these have prompted pharmacist-led antimicrobial stewardship initiatives such as pharmacist-ordered MRSA nasal swabs for patients receiving empiric antistaphylococcal antibiotic therapy for presumed pneumonia. One quasi-experimental study was performed by Pham and colleagues in their 350 community teaching hospital with a respiratory MRSA rate of 11% using PCR-based MRSA nasal swabs.16 In this institution, indications are required on any orders placed for antibiotic therapy. In patients receiving vancomycin or linezolid for any pneumonia indication without an extrapulmonary infection source, the pharmacist reviewing the antibiotic order could also order a STAT MRSA nasal swab per protocol without a physician order. The results of these nasal swabs were available 60 minutes after completion of the swab and when complete, the pharmacist would contact the provider regarding antibiotic de-escalation. In this study, 72 patients were included in the pre-implementation (physician required) group and 138 patients were included in the post-implementation (pharmacist-led) group. Notably, there were no patients with ventilator-associated pneumonia in either group. Compared with the pre-implementation group, the mean duration of intravenous vancomycin therapy decreased by 1.1 days (2.5 ± 1.3 days versus 1.4 ± 1.2 days, P <0.001) in all patients with pneumonia. In another community hospital study from Texas, Baby and colleagues published their findings supporting the implementation of nasal swab PCR testing as part of a pharmacist-led antimicrobial stewardship initiative.17 In this study, 27 patients were included in the pre-PCR testing group and 30 patients were included in the post-implementation cohort. Patients with healthcare-associated, community, and hospital-acquired pneumonia were enrolled. The use of nasal PCR testing decreased the mean duration of therapy active against MRSA by 46.6 hours (74.0 ± 48.9 hours versus 27.4 ± 18.7 hours, 95% confidence interval: 27.3 to 65.8 hours, P < 0.0001). There were no significant differences in days to clinical improvement, length of stay, or hospital mortality between groups.
Considering the relative challenge of obtaining high-quality respiratory specimens for culture in some patients, it would be prudent to consider the use of MRSA nasal swabs even in institutions where PCR testing is not available as a useful method of determining the need for MRSA therapy. A pharmacist-led approach may be an ideal method for promoting antimicrobial stewardship in this patient population without compromising clinical improvement.16,17
Staphylococcus aureus and coagulase-negative staphylococci are estimated to comprise ≥50% of osteomyelitis infections.18,19 For native vertebral osteomyelitis the IDSA guidelines note that blood cultures may be positive for Staphylococcus aureus in up to 50% of cases,11 and that it is recommended to collect blood cultures to assist in diagnosis and treatment. Considering that medical treatment for osteomyelitis often spans several weeks, proper identification of the infecting organism is strongly recommended by the IDSA,11 and bone biopsy is recommended as a standard of care. Likewise, there is a paucity of data available for the use of MRSA nasal swabs as a tool to prevent or de-escalate antibiotic regimens with activity against MRSA. Given this information, there is no recommendation that can be made for the use of MRSA nasal swabs in this disease state.
In 2008, Robicsek and colleagues published a retrospective cohort study analyzing the results of a universal MRSA nasal swab initiative at their 850-bed health system in Chicago, IL.20 In this study, the BD-GeneOhm real-time PCR test was used to analyze 57,089 nasal swabs. Of the total PCR tests obtained, 5,779 were performed within 24 hours of a positive culture. Culture sites included in the analysis are shown in Table 2. 1012 patients (18.5%) of patients received blood cultures. Of the confirmed cases of MRSA, 217 of 323 patients (67.2%) had a positive nasal PCR (confidence interval [CI]: 61.8, 72.3). Although two-thirds of patients with confirmed MRSA infections had positive MRSA nasal colonization, it could not be determined in this study if the infecting MRSA was identical to the colonizing MRSA strain. The nasal sampling results from this study are summarized in table 2.
From this study, the authors concluded that the negative predictive value derived in their patient population was high enough to consider using MRSA nasal swabs to rule out MRSA as an infecting organism in respiratory and bloodstream sources. They did, however, note that these results should be interpreted with caution due to the low prevalence of MRSA (5.6%) in their health system, and that the negative predictive value decreases as the disease prevalence increases. They also note the importance of the pre-test probability of MRSA infection as the MRSA nasal swab does have a relatively high false-negative risk. In conclusion, this study demonstrated that in an infection in any body site where MRSA accounts for ≤10% of isolates the negative predictive value is ≥96%, but decreases as the prevalence of MRSA infection increases. These findings stress the importance of institution-specific infection rates for correct interpretation of nasal swab testing campaigns.
Skin and Soft Tissue Infection
The 2014 IDSA guidelines for the diagnosis and management of skin and soft tissue infections do not recommend empiric anti-MRSA therapies for most patients with surgical site infections, simple cellulitis, erysipelas, or bite wounds.10 Despite these recommendations antibiotics active against MRSA are still frequently prescribed for common skin and soft tissue infections such as simple cellulitis without MRSA risk factors.21 The IDSA guidelines recognize the nares as an important predictor of MRSA skin and soft tissue infection. They recommend empiric anti-MRSA therapy in patients with a history of MRSA nasal colonization in both cellulitis and surgical site infections, and they also recommend nasal decolonization in patients with recurrent skin abscesses.10 In regards to simple cellulitis, a small retrospective study by Schleyer and colleagues22 assessed 52 patients with MRSA nasal swabs against cultures of their skin wounds. Superficial swabs were collected in cases of simple cellulitis without abscess (40% of cases) while 60% of cultures were collected from abscess fluid after incision and drainage. Staphylococcus species grew in 25 patients with 84% positive for MRSA. In this study, the nasal swab positive predictive value was 100% with a negative predictive value of 45% effectively ruling in MRSA, but failing to reliably rule-out disease. Superficial swabs are not recommended in simple cellulitis per the IDSA limiting the utility of this study, but these results may still support the use of an MRSA nasal swab as a tool to confirm the need for therapy active against MRSA in situations where these treatments are being considered. Of note, the IDSA does not currently have a stance on the use of MRSA nasal swabs to de-escalate therapy that has already started for these disease states.10
Decolonization of MRSA
Since MRSA nasal colonization has been associated with an increased risk of MRSA infection,3,4 decolonization of MRSA in known carriers is a strong consideration for improving infection rates. In a review by Troeman and colleagues in 2019,23 several potential ways to decrease MRSA colonization were highlighted including nasal mupirocin, chlorhexidine gluconate, povidone-iodine, trimethoprim/sulfamethoxazole, rifampicin, polyhexanide, and selective oropharyngeal decontamination. In this review, 54 trials were analyzed. There were very few high quality evidence trials that exclusively used one of the previously mentioned methods, however, mupirocin was found to have sufficient evidence to justify recommendations. The trials that analyzed mupirocin are summarized in Table 3.
Based on the data by Troeman and colleagues, decolonization of nasal S. aureus using mupirocin has varying effects on the risk of S. aureus infection rates. In known carriers receiving dialysis or elective surgery it is reasonable to pursue decolonization. In ICU patients, universal decolonization of carriers, non-carriers, and patients with unknown carrier status using both mupirocin and daily bathing with chlorhexidine could be considered as an initiative to reduce MRSA infections in units with a significant disease burden.
Organism Detection After Anti-MRSA Therapy
In most infectious diseases, the initiation of antibiotic therapy before collection of culture risks decreasing yield resulting in continuation of broad-spectrum antibiotics when more narrow therapies would be appropriate.5-12 Given this paradigm, collection and interpretation of an MRSA nasal swab after initiation of antistaphylococcal antibiotics may be met with hesitation. In 2014, Shenoy and colleagues published a randomized controlled trial that enrolled 259 patients that were tested with both culture-based and PCR-based MRSA nasal swab methods.35 132 patients (51%) were tested within 48 hours of starting antistaphylococcal antibiotics and 127 (49%) patients were tested in the absence of antibiotics. There was strong concordance between the culture and PCR-based methods in the absence of antibiotics (93.7% concordance; 95% CI, 88.1%, 96.8%). There were also no differences in the proportion of positive results between methods without concurrent antibiotics (33.1% for culture, and 36.2% for PCR-based; P = 0.29). When tested in the presence of antibiotics, concordance remained strong (90.9%; 95% CI: 84.8%, 94.7%). There was a higher amount of positive results in the PCR method compared to the culture method when tested with concurrent antibiotics (41.7% and 34.1% respectively; P < 0.01). The authors of this study postulated that the decreased yield in the culture group may have been due to a decline in viable organisms, while the PCR method may have retained positive results due to the ability to detect DNA from non-viable organisms. Based on the results of this study, it may be reasonable to collect and analyze MRSA nasal swab results even in the presence of antistaphylococcal antibiotics if collected within the first 48 hours of therapy in institutions that use a PCR-based method.
In conclusion, MRSA nasal swabs can help detect patients that have a higher risk of MRSA infection based on their colonization status. MRSA nasal swabs can serve the clinician as an effective tool for antimicrobial stewardship, with more reliable results in those disease states with a low prevalence of MRSA. Pneumonia remains the disease state with the best evidence support for the use of MRSA nasal swabs. The 2019 community acquired pneumonia guideline recommendations strongly encourage the use of these swabs when deciding on empiric antibiotics and de-escalation prior to respiratory culture results.6 Likewise, in patients where a bloodstream infection is suspected, the high negative predictive value demonstrated by Robicsek and colleagues may allow the use of MRSA nasal swabs to de-escalate empiric anti-MRSA therapy.20 Cautious interpretation of the study results summarized is still encouraged including a local comparison of MRSA infection rates. It should also be noted that current evidence for the use of MRSA nasal swabs is fairly poor in osteomyelitis and skin and soft tissue infections, with weak recommendations that could be made to continue MRSA therapy in those patients with a positive nasal screen being treated for cellulitis and skin abscess.10,22 When MRSA is detected, decolonization regimens with mupirocin may be beneficial to reduce the risk of MRSA infection if the patient is on dialysis or scheduled for a surgical procedure.24-30 Even after starting antistaphyloccal antibiotics, an MRSA screen may still be useful when conducted within 48 hours from the start of therapy, and more reliable if a PCR method for organism detection is used.35
By: Shannon Jones, PharmD
Acute respiratory distress syndrome (ARDS) is a type of acute, diffuse inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight and loss of aerated lung tissue. The LUNG SAFE study in 2016 found that ARDS accounts for ~10% of ICU admissions and 23% of ventilated patients. The mortality rate has been reported as high as 25 – 40% in most studies. The main causes (~85% of cases) of ARDS include pneumonia (bacterial, viral, fungal, or opportunistic), aspiration of gastric contents, and sepsis from non-pulmonary sources. Pathophysiology of ARDS includes three distinct phases: exudative, proliferative, and fibrotic as follows:
Definition of ARDS1,3,5,6
The Berlin Definition, essentially a modification of the AECC Definition (1994), established ARDS severity categories (i.e. mild [PaO2/FiO2 ratio 200-300 mmHg], moderate [PaO2/FiO2 ratio 100-200 mmHg], and severe [PaO2/FiO2 ratio < 100 mmHg]) that are predictive of increased mortality and increased duration of mechanical ventilation. The Berlin defines ARDS as an acute onset of impaired oxygenation (PaO2/FiO2 ratio < 300 mmHg) with PEEP > 5 cm H2O + bilateral opacities – not fully explained by effusions, lobar/lung collapse, or nodules + respiratory failure not fully explained by cardiac failure or fluid overload.
Neuromuscular Blocking Agents3,6,7
Neuromuscular blocking agents (NMBAs) block neural transmission at the myoneural junction. Depolarizing NMBAs mimic acetylcholine and provide continuous depolarization of the action potential. Non-depolarizing NMBAs bind directly to cholinergic receptor sites and prevent the subsequent action potentials. The intended beneficial use in ARDS includes ensuring patient-ventilator synchrony and reducing the risk of ventilator-associated lung injury. Concerns that arise when using NMBAs include ICU-acquired weakness, thrombosis and thromboembolism, and patient awareness during paralysis. Some disease states have potential to increase or decrease efficacy of these agents such as burns, electrolyte abnormalities, and trauma. Monitoring of NMBAs is required to ensure adequate depth of neuromuscular blockade and is performed with the use of peripheral nerve stimulator AKA Train-of-Four (TOF) which stimulates specific muscles to assess the extent of the blockade.
Treatment Recommendations + Proposed Treatment Algorithm
When considering the use of NMBAs in ARDS, cisatracurium is the ideal paralytic based on pharmacokinetic and adverse effect profile for hemodynamically unstable patients; metabolism is by Hofmann elimination which avoids hepatic and renal dysfunction. Non-pharmacologic treatment strategies are centered around lung-protective ventilation and conservative fluid management (i.e. low tidal volume, high PEEP, monitoring of equal fluid input and output).