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Feb 2019 FAQs

Can alteplase be used to clear occluded chest tubes?

What is the latest evidence on alternatives to magnesium sulfate in patients with preeclampsia and eclampsia?

What are the Infectious Diseases Society of America recommendations for the diagnosis and management of seasonal influenza?

Answers

Can alteplase be used to clear occluded chest tubes?

Introduction

Thoracotomy tubes, (more commonly known as chest tubes or pleural catheters) are used to drain unwanted air, fluid (blood, pus, chyle, and serous fluids), or blood clots from the pleural space (ie, the area between the chest wall and the lungs).1,2 Alternatively, these devices can be used to deliver intrapleural drug therapy, restore negative pressure in the pleural cavity, or expand a collapsed lung.1,3 Conditions that may necessitate the need for placement of a chest tube include pneumothorax, complicated parapneumonic effusions (ie, empyemas), and trauma or injury to the chest wall.1 

Occlusion of chest tubes is one of the primary causes of pleural drain failure.4 The incidence of tube blockage varies widely in the literature, but rates up to 64% have been reported for patients with empyema. One common sign of an occluded chest tube is lack of fluid movement in the tube upon coughing or respiration.5 Causes of a blocked tube may include kinking, angulation, clot formation, or the presence of debris of lung tissue. Blockage is also more common in small-bore drains.6,7 Depending on the initial need for placement, an occluded tube will often halt improvement of a patient’s clinical status, as there will be ineffective drainage of unwanted pleural collections or insufficient delivery of intrapleural medication; tension pneumothorax can also occur in cases of ongoing air leak.5

Standards of care

Once chest tube blockage has been identified, strategies for management of this complication are not standardized.8 However, the tube should first be checked for kinks and unkinked if applicable.3,5,9 In a 2005 British Thoracic Society (BTS) guideline for the management of pleural infections in children, recommendations for unclogging blocked drains include flushing the drain with normal saline or allowing urokinase (a fibrinolytic not available in the US) to dwell in the catheter.9 Aside from these recommendations, other applicable guidelines for pleural diseases do not specify a preferred method for unclogging blocked pleural drains.6,7 Two other BTS guidelines published in 2010 acknowledge data for the use of regular flushing with saline or a fibrinolytic drug to prevent tube blockage and note that these strategies may be helpful. However, BTS does call out the need for more data for the use of regular flushing for this purpose, and also notes that disconnecting larger drains for the purpose of irrigation may introduce secondary infections. More recent guidelines for the management of empyema from the American Association for Thoracic Surgery similarly do not provide recommendations for the management of blocked pleural drains, but again recommend routine flushing as a preventative strategy.10

Other techniques for unblocking an obstructed chest tube that are described in the literature include milking or stripping tubes. This is controversial, however, as the negative pressure created by this technique may damage lung tissue.3,5 For chest tubes that are unable to be unblocked, removal and replacement is usually required.6,7  

Alteplase for restoring chest tube patency

Thrombolytic therapy has long been used to restore blocked central venous access devices (CVADs), however, the use of thrombolytics to unclog chest tubes is less understood.8 Alteplase is a thrombolytic agent that works by binding to fibrin within a clot and activating the transformation of plasminogen to plasmin, thereby rapidly dissipating clots.11 While this agent is more commonly used for patients with acute ischemic conditions, one formulation of this product (Cathflo® Activase®) is specifically approved for restoring the function of CVADs. Alteplase is also used off-label for intrapleural administration in the management of parapneumonic effusion and empyema.11 Data supporting the intrapleural use of alteplase for these indications is outside of the scope of this article, but for reference, the doses used for this these indications generally range from 10 to 100 mg.11,12

Literature describing the use of alteplase to restore patency to occluded chest tubes and pleural catheters is sparse. The most robust evidence to support this use comes from a 2015 single-center retrospective study by Wilshire et al.8 Thirty-five patients with pleural effusion managed with a tunneled pleural catheter (TPC; 37 TPCs in total) and who received alteplase for catheter obstruction were identified. The majority of pleural effusions in the study were malignant in nature (57%) and 86% of patients were undergoing chemotherapy. Investigators defined TPC obstruction as a sudden reduction of pleural drainage to less than 10 mL, along with imaging demonstrating fluid in the thorax. In an attempt to unblock obstructed TPCs, alteplase 2 mg vials were reconstituted with sterile water to a concentration of 1 mg/mL and doses ranging from 2 to 5 mg were instilled into the catheter. The solution was allowed to dwell for 1 to 2 hours and was then drained from the catheter. Efficacy in resorting TPC patency was defined as pleural drainage greater than 10 mL and a return of effective flow. Of the 37 TPCs evaluated, all obstructed catheters had a return of function after instillation of alteplase. An initial episode of catheter re-obstruction occurred in 10 of the initial 37 TPCs after a median of 1 month, but all were successful retreated with alteplase. An additional 5 catheters required a third instillation of alteplase and 3 required a fourth, but again all were successfully unclogged and no TPCs in the study were removed due to blockage. Authors reported that there were no bleeding complications related to treatment.

Another multi-center retrospective study of neonatal intensive care units (NICU) evaluated the efficacy of alteplase in resorting patency of 168 occluded catheters.13 Only 7 (5%) catheters in 5 neonates in this study were identified as chest tubes. Of these 7 tubes, 4 were unblocked after 1 dose of alteplase. An additional 2 of 3 tubes were successfully unclogged after a second dose of alteplase and 1 tube was unblocked after a third dose of alteplase. The exact dose of alteplase used in this study was not specified, but authors note that 2 mg vials of the Cathflo® Activase® product were used. One new case of bleeding (intraventricular hemorrhage) was identified within 24 hours of alteplase administration in a neonate who received 3 doses of alteplase within a 6-hour period; one of these doses was for an occluded chest tube and the other two were for central lines. The association of this bleeding event to use of alteplase for unblocking the catheters was unclear.

Authors of the aforementioned study of NICU patients also found significant cost savings with the use of alteplase for unclogging obstructed catheters.13 While the total cost of 205 doses alteplase in 169 neonates was approximately $35,875, the estimated cost savings to the institution by not having to replace occluded catheters was about $28,860. Therefore, the net cost of using alteplase to unblock each occluded catheter was about $34. Cost-savings should be interpreted with caution as data includes mostly catheters other than chest tubes.

Lastly, anecdotal data for the use of alteplase to clear occluded chest tubes is described in a 2011 review article by Hogg et al.3 Authors suggest the use of a 1 mg/mL alteplase solution in sterile saline in a volume sufficient to fill the chest tube lumen; a dwell time of 10 to 30 minutes is suggested. 

Conclusion

Chest tube occlusion is one of the major causes of pleural drain failure. Alteplase 1 mg/mL solution has been used to restore patency of occluded TPCs and chest tubes with excellent success rates, even when multiple retreatments are required. Individual alteplase doses of 2 to 5 mg were reported in one study, but other literature suggests using tube size to guide how much total volume of the 1 mg/mL solution to use. Overall, this strategy has generally not demonstrated any significant safety risks and is likely cost-effective because of its ability to decrease the need for much more costly removal and replacement of occluded and nonfunctional chest tubes.  

References

  1. Allen BR and Ganti L. Chest Tube Thoracostomy. In: Ganti L, ed. Atlas of Emergency Medicine Procedures. New York, NY: Springer; 2016. https://link.springer.com/chapter/10.1007/978-1-4939-2507-0_23#citeas. Accessed January 17, 2019.
  2. Abramovitz J. Chest Tube Insertion. In: Tscheschlog BA, ed. Lippincott Nursing Procedures. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015. http://ovidsp.tx.ovid.com/sp-3.27.1a/ovidweb.cgi?&S=KEJCFPFMDHDDEPDNNCFKJFFBIMHAAA00&tab=books&C=books&Jump+to+Browse=books&New+Database=S.dbListAll%7cSingle%7c20. Accessed January 17, 2019.
  3. Hogg JR, Caccavale M, Gillen B, et al. Tube thoracostomy: a review for the interventional radiologist. Semin Intervent Radiol. 2011;28(1):39-47.
  4. Shen KR, Bribriesco A, Crabtree T, et al. The American Association for Thoracic Surgery consensus guidelines for the management of empyema. J Thorac Cardiovasc Surg. 2017;153(6):e129-e146.
  5. Kesieme EB, Dongo A,  Ezemba N, Irekpita E, Jebbin N, Kesieme C. Tube thoracostomy: complications and its management. Pulm Med. 2012; 56878.
  6. Havelock T, Teoh R, Laws D; on behalf of the BTS Pleural Diseaes Guideline Group. Pleural procedures and thoracic ultrasound: British Thoracic Society pleural disease guideline 2010. Thorax. 2010;65(Suppl 2):61-76.
  7. Davies HE, Davies RJ, Davies CW, British Thoracic Society (BTS) Pleural Disease Guideline Group. Management of pleural infection in adults: BTS Pleural Disease Guideline. 2010. Thorax. 2010;65 Suppl 2:ii41-53.
  8. Wilshire CL, Louie BE, Aye RW, Farivar AS, Vallieres E, Gorden JA. Safety and efficacy of fibrinolytic therapy in restoring function of an obstructed tunneled pleural catheter. Ann Am Thorac Soc. 2015;12(9):1317–1322.
  9. Balfour-Lynn IM, Abrahamson E, Cohen G, et al. BTS guidelines for the management of pleural infection in children. Thorax. 2005;60 Suppl 1:i1-21.
  10. Shen KR, Bribriesco A, Crabtree T, et al. The American Association for Thoracic Surgery consensus guidelines for the management of empyema. J Thorac Cardiovasc Surg. 2017;153(6):e129-e146.
  11. Lexicomp [database online]. Hudson, OH: Wolters Kluwer Health, Inc; 2019. http://www.lexicomp.com. Accessed January 17, 2019.
  12. Hamblin SE and Furmanek DL. Intrapleural tissue plasminogen activator for the treatment of parapneumonic effusion. Pharmacotherapy. 2010;30(8):855-862.
  13. Scott DM, Ling CY, MacQueen BC, Baer VL, Gerday E, Christensen RD. Recombinant tissue plasminogen activator to restore catheter patency: efficacy and safety analysis from a multihospital NICU system. J Perinatol. 2017;37(3):291-295.

Prepared by:

Katherine Sarna, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

February 2019

The information presented is current as January 17, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the latest evidence on alternatives to magnesium sulfate in patients with preeclampsia and eclampsia?

Background

Magnesium sulfate has long been the standard of care for seizure prevention in pregnant women with severe preeclampsia and eclampsia.1,2 Numerous clinical trials support the efficacy of magnesium sulfate in the setting of preeclampsia and a large systematic review reported significant reductions in the risk of eclampsia and placental abruption with magnesium sulfate compared to placebo.2,3 Some clinicians also use magnesium sulfate on a case by case basis to prevent seizures in women with preeclampsia without severe features.2 Treatment of eclampsia-related seizures should include magnesium sulfate to prevent recurrent seizures and maternal mortality.

Recent shortages in magnesium sulfate injection have prompted clinical interest in alternative medications for preventing preeclampsia-related seizures.4  Due to evidence demonstrating superior efficacy of magnesium sulfate, a 2019 guidance from the American College of Obstetricians and Gynecologists (ACOG) states that alternative medications including benzodiazepines and phenytoin should only be used when magnesium sulfate is contraindicated (eg, myasthenia gravis, hypocalcemia, moderate to severe renal failure, heart block or ischemia, or myocarditis) or not available, or if the patient is receiving antiepileptic medications.2  For prevention of recurrent seizures in patients with eclampsia, ACOG recommends magnesium sulfate due to superior efficacy compared to phenytoin or diazepam.

This article summarizes clinical evidence of alternatives to magnesium sulfate in patients with preeclampsia and eclampsia, including phenytoin, benzodiazepines, and nimodipine.

Literature Review

Preeclampsia

Several controlled trials and systematic reviews describe the comparative efficacy of magnesium sulfate and phenytoin, diazepam, or nimodipine for seizure prevention in patients with preeclampsia (Table 1).3,5-10 Phenytoin has been compared to magnesium in the largest number of patients. Magnesium consistently resulted in fewer seizures than phenytoin but seizure rates in patients receiving phenytoin were very low overall (≤4% depending on the study).5,7,8 Phenytoin therapy may also be associated with a lower rate of cesarean delivery compared to magnesium.3,5,6,7 Dosing varied between studies but no studies reported additional safety concerns with phenytoin.3,5-8 Comparative data with diazepam or nimodipine versus magnesium is limited to one trial each.9,10 There is not enough data to make any conclusions about seizure prevention, but diazepam was associated with more maternal morbidity than magnesium in a retrospective, observational study.9 Nimodipine was less effective than magnesium but may have favorable effects on maternal morbidity.10

 Table 1. Comparative Clinical Evidence for Magnesium Sulfate Alternatives for Preeclampsia.3,5-10

Study design and population

Interventions

Major comparative outcomes

Phenytoin

Khooshideh 20175

RCT, mild/severe preeclampsia (n=350)

Phenytoin 20 mg/kg IV over 20 minutes, then 500 mg orally after 10 hours

Magnesium sulfate 4 g IV over 20 minutes followed by 2 g/hour IV infusion

  • Seizures occurred in no patients in the magnesium group and 7 patients in the phenytoin group with severe preeclampsia
  • Magnesium was associated with longer duration of labor and increased rate of cesarean delivery

Duley 20103

Systematic review, preeclampsia

Phenytoin vs magnesium sulfate (4 trials)

  • Lower risk of eclampsia with magnesium (RR 0.08, 95% CI 0.01 to 0.6)
  • Higher risk of cesarean delivery with magnesium (RR 1.21, 95% CI 1.04 to 1.4)
  • No differences in: maternal morbidity, neonatal morbidity or mortality

Chien 19966

Systematic review, preeclampsia

Phenytoin vs magnesium sulfate (3 trials)

  • Lower risk of seizure with magnesium (OR 0.15, 95% CI 0.03 to 0.72)
  • Higher risk for cesarean delivery with magnesium (OR 1.27, 95% CI 1.06 to 1.54)
  • No differences in: maternal mortality, neonatal mortality

Lucas 19957

RCT, HTN in labor/preeclampsia (n=2138)

Phenytoin 1 g IV over 1 hour, then 500 mg orally after 10 hours

Magnesium sulfate 10 g IM in 2 divided doses followed by 5 g IM every 4 hours; patients with severe preeclampsia also received a 4 g IV loading dose

  • Seizure occurred in 10 patients in the phenytoin group and no patients in the magnesium group (p=0.004)
  • Significantly more cesarean delivery occurred in the magnesium group (p=0.047), which the authors attributed to factors other than the intervention
  • No differences in: neonatal morbidity or mortality, NICU admission, maternal outcomes

Friedman 19938

RCT, preeclampsia (n=103)

Phenytoin 1 to 1.5 g IV loading dose followed by maintenance doses titrated to serum levels

Magnesium sulfate 6 g IV followed by 2 g/hour IV infusion

  • No seizures occurred in either group
  • No differences in: cesarean delivery, maternal morbidity, neonatal morbidity
  • Rate of cervical dilation was faster in the phenytoin group (p=0.016), even after adjusting for confounders

Diazepam

Kassie 20149

Cross-sectional study, severe preeclampsia (n=231)

Diazepam

Magnesium sulfate

(dosing not specified)

  • Seizures occurred in 1 woman in the magnesium group and 3 women in the diazepam group (p-value not reported)
  • Maternal morbidities were less common with magnesium vs diazepam (6.9% vs 15%, p=0.001)
  • Hospital LOS was longer with diazepam vs magnesium (p=0.016)
  • No differences in ICU admission

Chien 19966

Systematic review, preeclampsia

Diazepam vs magnesium sulfate (1 trial)

  • Seizure outcomes not reported
  • No differences in: neonatal mortality, cesarean delivery

Nimodipine

Duley 20103

Systematic review, preeclampsia

Nimodipine vs magnesium sulfate (1 trial)

  • Lower risk of eclampsia with magnesium (RR 0.33, 95% CI 0.14 to 0.77)
  • Higher risk for needing antihypertensive drugs with magnesium (RR 1.19, 95% CI 1.08 to 1.31)
  • No differences in: neonatal morbidity or mortality

Belfort 200310

RCT, severe preeclampsia (n=1650)

Nimodipine 60 mg orally every 4 hours

Magnesium sulfate 6 g loading dose followed by 2 g/hour IV infusion, or 4 g loading dose followed by 1 g/hour IV infusion

  • Seizure was more common in the nimodipine group (RR 3.0, p=0.01)
  • Need for hydralazine and postpartum hemorrhage were more common with magnesium (p<0.001 and p=0.03, respectively)
  • No differences in: neonatal outcomes, maternal outcomes, mode of delivery

Abbreviations: CI=confidence interval; HTN=hypertension; ICU=intensive care unit; IM=intramuscular; IV=intravenous; LOS=length of stay; NICU=neonatal intensive care unit; OR=odds ratio; RCT=randomized controlled trial; RR=relative risk.

Eclampsia

Several clinical trials and systematic reviews have compared magnesium sulfate and phenytoin or diazepam for seizure prevention in patients with eclampsia (Table 2).5,6,11-16 The results of all studies support superior efficacy of magnesium in preventing recurrent seizures. Diazepam has been compared to magnesium in more patients than phenytoin; rates of recurrent seizures with these 2 medications is fairly comparable (10% to 30% with diazepam vs 12% to 40% with phenytoin) and neither medication has been associated with unexpected safety concerns.5,9,11,13,14,16 Several studies also suggest beneficial effects of magnesium on maternal and neonatal morbidity.

  Table 2. Comparative Clinical Evidence for Magnesium Sulfate Alternatives for Eclampsia.5,6,11-16

Study design and population

Interventions

Major comparative outcomes

Phenytoin

Khooshideh 20175

RCT, eclampsia (n=50)

Phenytoin 20 mg/kg IV over 20 minutes, then 500 mg orally after 10 hours

Magnesium sulfate 4 g IV over 20 minutes followed by 2 g/hour IV infusion

  • Seizures occurred in no patients in the magnesium group and 3 patients in the phenytoin group
  • Magnesium was associated with longer duration of labor and increased rate of cesarean delivery

Roy 201311

RCT, eclampsia (n=80)

Phenytoin 10 mg/kg IV initially followed by 5 mg/kg after 2 hours, then 300 mg IV (frequency of dosing during maintenance phase not specified)

Magnesium sulfate 4 g IVP followed by 5 g IM every 4 hours

  • There were no patients with recurrent seizures in the magnesium group vs 7 in the phenytoin group (p=0.032)
  • Return to consciousness was faster in the phenytoin group (p<0.0001)
  • No difference between groups in: number of convulsions, level of consciousness, time from first seizure to delivery, outcomes related to neonatal morbidity or mortality

Duley 201012

Systematic review, eclampsia

Phenytoin vs magnesium sulfate (6 trials)

  • Lower risk of seizure with magnesium (RR 0.34, 95% CI 0.24 to 0.49)
  • Lower risk of maternal pneumonia with magnesium (RR 0.44, 95% CI 0.24 to 0.79)
  • Lower risk of ICU admission (RR 0.67, 95% CI 0.5 to 0.89) and need for ventilation (RR 0.68, 95% CI 0.5 to 0.91) with magnesium
  • Lower risk of special care baby unit stay and less time in special care baby unit with magnesium
  • No differences in: maternal mortality, other maternal morbidity outcomes, neonatal mortality or morbidity

Sawhney 199913

RCT, eclampsia (n=50)

Phenytoin 10 mg/kg IV initially followed by 5 mg/kg after 2 hours, then 500 mg IV given 12 hours after completing the loading dose followed by 250 mg orally or IV every 12 hours for 4 doses

Magnesium sulfate 4 g IV and 8 g IM, followed by 4 g IM every 4 hours

  • Recurrent seizures occurred in 2 patients in the magnesium group and 10 patients in the phenytoin group
  • Duration of labor was longer in the magnesium group (mean 10.3 vs 8.86 hours, p<0.05) and birth weight was higher (p<0.05)
  • No difference between groups in: mode of delivery, hospital LOS, neonatal or maternal morbidity or mortality

Chien 19966

Systematic review, eclampsia

Phenytoin vs magnesium sulfate (2 trials)

  • Lower risk of seizure with magnesium (OR 0.27, 95% CI 0.17 to 0.45)
  • No difference in: maternal mortality, neonatal mortality, cesarean delivery

Collaborative Eclampsia Trial (no authors) 199514

RCT, eclampsia (n=777)

Phenytoin 1 g IV given over 20 minutes followed by 100 mg every 6 hours (plus diazepam 10 mg IV for immediate seizure control)

Magnesium sulfate 4 g IVP and 5 g IM into each buttock followed by 5 g IM every 4 hours, or 4-5 g IV followed by 1 g/hour IV infusion

  • Recurrent seizures were less common with magnesium (p<0.00001)
  • Maternal pneumonia, need for ICU, and blood transfusion were lower with magnesium (p=0.005, p=0.004, and p=0.03)
  • Infants in the magnesium group had higher 1-minute APGAR scores, less intubation, and less need for NICU (p=0.005, p=0.0009, p=0.0004)
  • No difference between groups in: maternal mortality, labor induction, and cesarean delivery

Diazepam

Kassie 20149

Cross-sectional study, eclampsia (n=126)

Diazepam

Magnesium sulfate

(dosing not specified)

  • Seizures after medication treatment occurred in 2 woman in the magnesium group and 8 women in the diazepam group (p=0.038)
  • Maternal morbidities were less common with magnesium vs diazepam (7 women vs 26 women, p<0.001)
  • 2 women in the magnesium group died vs 4 in the diazepam group
  • No differences in: ICU admission, hospital LOS

Duley 201015

Systematic review, eclampsia

Diazepam vs magnesium sulfate (7 trials)

  • Lower risk of maternal death with magnesium (RR 0.59, 95% CI 0.38 to 0.92)
  • Lower risk of recurrent seizures with magnesium (RR 0.43, 95% CI 0.33 to 0.55)
  • APGAR scores were higher at 1 minute and 5 minutes with magnesium
  • LOS in special care baby unit was lower with magnesium
  • No differences in: maternal morbidity, ICU admission, neonatal mortality, or other measures of neonatal morbidity

Shamsuddin 199816

RCT, eclampsia (n=200)

Diazepam 10 mL loading dose (concentration and route not specified) followed by 40 mg/500 mL given as a maintenance infusion (rate not specified)

Magnesium sulfate 4 g IV and 6 g IM followed by 2.5 g IM every 4 hours

  • Recurrent seizures occurred in 26% of the diazepam group vs 5% of the magnesium group (p<0.0005)
  • Time to seizure control, time to regain consciousness, and time to blood pressure control were less in the magnesium group (p-values not reported)
  • 3 patients in the magnesium group and 7 patients in the diazepam group died
  • 5 patients in the diazepam group experienced deep sedation after treatment
  • No differences in: need for cesarean delivery, need for NICU, neonatal morbidity

Chien 19966

Systematic review, eclampsia

Diazepam vs magnesium sulfate (2 trials)

  • Lower risk of seizure with magnesium (OR 0.42, 95% CI 0.3 to 0.57)
  • No difference in: maternal mortality, neonatal mortality, cesarean delivery

Collaborative Eclampsia Trial (no authors) 199514

RCT, eclampsia (n=910)

Diazepam 10 mg IVP repeated until seizure control followed by 40 mg/500 mL IV infusion over 24 hours then 20 mg/500 mL IV infusion over 24 hours (infusion rate titrated to level of consciousness)

Magnesium sulfate 4 g IVP and 5 g IM into each buttock followed by 5 g IM every 4 hours, or 4 to 5 g IV followed by 1 g/hour IV infusion

  • Recurrent seizures were less common with magnesium (p<0.00001)
  • NICU LOS >7 days was less common with magnesium (p=0.04)
  • No difference between groups in: maternal morbidity or mortality, labor induction, cesarean delivery, neonatal mortality

Abbreviations: APGAR=scoring system for neonatal clinical status that consists of color, heart rate, reflexes, muscle tone, and respiration; CI=confidence interval; ICU=intensive care unit; IM=intramuscular; IV=intravenous; IVP=intravenous push; LOS=length of stay; NICU=neonatal intensive care unit; OR=odds ratio; RCT=randomized controlled trial; RR=relative risk.

Conclusion

Women with gestational hypertension and/or preeclampsia require close monitoring and blood pressure control with appropriate antihypertensive therapy.1,2 Eclampsia is associated with adverse maternal and fetal outcomes and the use of medications to prevent seizures in this population is the standard of care. Guidance from ACOG endorses the preferential use of magnesium sulfate in patients with preeclampsia and eclampsia due to superior efficacy compared to other medications.2 Alternative medications can be used if magnesium is not available (including phenytoin and benzodiazepines) but evidence supporting their efficacy is limited. Doses have varied and many studies did not have adequate power to find differences in seizure incidence, mortality, or other outcomes. Another limitation is that much of the comparative evidence is from other countries so outcomes may not fully reflect current clinical practice in the United States. Overall, phenytoin seems to have reasonable efficacy and safety in patients with preeclampsia.3,5-8 For eclampsia, rates of recurrent seizure with phenytoin and diazepam are comparable but fairly high.5,9,11,13,14,16  In the context of magnesium sulfate injection shortages, clinicians should consider allocating available supply to pregnant patients with preeclampsia or eclampsia, if possible.

References

  1. Ward KE. Pregnancy and lactation: therapeutic considerations. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=1861&sectionid=146066717. Accessed January 23, 2019.
  2. ACOG Practice Bulletin No. 202: gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133(1):e1-e25.
  3. Duley L, Gülmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev. 2010;(11):CD000025.
  4. American Society of Health-System Pharmacists. Current Drug Shortages. https://www.ashp.org/drug-shortages/current-shortages. Accessed January 18, 2019.
  5. Khooshideh M, Ghaffarpour M, Bitarafan S. The comparison of anti-seizure and tocolytic effects of phenytoin and magnesium sulphate in the treatment of eclampsia and preeclampsia: A randomised clinical trial. Iran J Neurol. 2017;16(3):125-129.
  6. Chien PF, Khan KS, Arnott N. Magnesium sulphate in the treatment of eclampsia and pre-eclampsia: an overview of the evidence from randomised trials. Br J Obstet Gynaecol. 1996;103(11):1085-1091.
  7. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333(4):201-205.
  8. Friedman SA, Lim KH, Baker CA, Repke JT. Phenytoin versus magnesium sulfate in preeclampsia: a pilot study. Am J Perinatol. 1993;10(3):233-238.
  9. Kassie GM, Negussie D, Ahmed JH. Maternal outcomes of magnesium sulphate and diazepam use in women with severe pre-eclampsia and eclampsia in Ethiopia. Pharm Pract (Granada). 2014;12(2):400.
  10. Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348(4):304-311.
  11. Roy J, Mitra JK, Pal A. Magnesium sulphate versus phenytoin in eclampsia - Maternal and foetal outcome - A comparative study. Australas Med J. 2013;6(9):483-495.
  12. Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Syst Rev. 2010;(10):CD000128.
  13. Sawhney H, Sawhney IM, Mandal R, Subramanyam, Vasishta K. Efficacy of magnesium sulphate and phenytoin in the management of eclampsia. J Obstet Gynaecol Res. 1999;25(5):333-338.
  14. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345(8963):1455-1463.
  15. Duley L, Henderson-Smart DJ, Walker GJ, Chou D. Magnesium sulphate versus diazepam for eclampsia. Cochrane Database Syst Rev. 2010;(12):CD000127.
  16. Shamsuddin L, Rouf S, Khan JH, Tamanna S, Hussain AZ, Samsuddin AK. Magnesium sulphate versus diazepam in the management of eclampsia. Bangladesh Med Res Counc Bull. 1998;24(2):43-48.

Prepared by:

Heather Ipema, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

February 2019

The information presented is current as of January 18, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are the Infectious Diseases Society of America recommendations for the diagnosis and management of seasonal influenza?

Background

Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses.1 The prevalence and severity of seasonal influenza varies from year to year. During the 2017-2018 season, the influenza burden was particularly severe, and its impact was the highest since the 2009 pandemic. It is estimated that 48.8 million people contracted the influenza virus and these illnesses lead to 959,000 hospitalizations and 79,400 deaths.

New guideline

The Infectious Diseases Society of America (IDSA) published an updated guideline on the diagnosis and management of seasonal influenza in December 2018, updating their previous 2009 guideline.2 Since the publication of the previous guideline, new diagnostic techniques have been developed and new antivirals have been approved. The guideline addresses diagnosis, treatment, chemoprophylaxis, and institutional outbreak control. Influenza prevention is not addressed as the Advisory Committee on Immunization Practices provides this information on an annual basis.

Diagnosis of influenza

Influenza testing is a useful tool in the clinical management of patients presenting with influenza-like symptoms or in patients who are presenting with exacerbations of certain co-morbid conditions, such as chronic lung disease.2 Clinicians need to consider both the likelihood of the patient symptoms aligning with influenza, along with the local influenza activity. Generally, recommendations for screening for influenza are stronger during periods of influenza activity. Key recommendations from the IDSA guideline are summarized in Table 1.

Table 1. Selected recommendations for the diagnosis of influenza.2*

Recommendation

LOE

Comments

In the outpatient setting or the ED, test for influenza if testing results will influence clinical management in:

If testing is not feasible or if the results will not influence clinical management, a clinical diagnosis of influenza can be made without testing.

  • High-risk patients¥ who present with influenza-like illness, pneumonia, or nonspecific respiratory illness

A-III

  • Patients who present with acute onset of respiratory symptoms with or without fever, and either exacerbation of a comorbid condition or known influenza complication 

A-III

For hospitalized patients, test for influenza on admission in:

Influenza testing is recommended in all hospitalized patients as it helps inform IPC measures and can reduce unnecessary use of antibiotics and antivirals.

  • Patients with acute respiratory illness, with or without fever

A-II

  • Patients with acute worsening of a chronic cardiopulmonary disease

A-III

  • Patients who are high-risk or immunocompromised and present with acute onset of respiratory symptoms

A-III

RT-PCR or other molecular assays are recommended for hospitalized patients to detect influenza

A-II

RT-PCR assays have high sensitivity and very high specificity. Rapid influenza diagnostic tests are only recommended as point-of-care assays due to their low to moderate sensitivity.

More information on algorithms and diagnostic tests can be found on the CDC website.3

* Recommendations and LOE are specific to periods of influenza activity; separate recommendations are provided in the guideline for times with low influenza activity.

†Strength of recommendation: A, good evidence; B, moderate evidence; C, poor evidence. Quality of evidence: I, evidence from ≥1 properly randomized controlled trials; II, evidence from ≥1 well-designed clinical trial or from cohort or case-controlled studies or multiple time-series; III, expert opinion based on clinical experience, descriptive studies or reports of expert committees.

¥ High-risk patients are those who are at high risk for developing serious influenza-associated complications; groups of people who are at high risk can be found at: https://www.cdc.gov/flu/about/disease/high_risk.htm4

Abbreviations: ED, emergency department; IPC, infection prevention and control; LOE, level of evidence.

Antiviral treatment

Antivirals should be initiated as soon as possible in suspected or confirmed influenza in any person who is hospitalized, outpatients with severe or progressive illness or those at high-risk of complications, children ≤2 years, adults ≥65 years, and pregnant women (including women who are within 2 weeks postpartum).2 While the treatment benefits of antivirals are greater with very early use, for hospitalized patients and those with severe or progressive illness, it is recommended that antivirals should be started regardless of the illness duration. The guideline recommends treatment using oral oseltamivir, inhaled zanamivir, or intravenous peramivir. Considerations for currently available antivirals is presented in Table 2.

While the IDSA and Centers for Disease Control and Prevention (CDC) recommend any neuraminidase inhibitor can be used in the treatment of influenza, oseltamivir is the preferred option.2,5 Particularly for critically ill patients, oseltamivir has been the most widely studied. With regard to dosing, the most recent evidence suggests that high-dose oseltamivir does not improve clinical outcomes even though high-dose oseltamivir had been previously recommended over standard dosing in certain clinical scenarios.6,7 Available pharmacokinetic studies also suggest that enteric administration of oseltamivir provides adequate exposure of the drug and that the drug can be given without dose modification in patients on extracorporeal membrane oxygenation.8-12 However, dose modification may be needed in patients on continuous renal replacement.

In cases where oseltamivir cannot be given, peramivir has the most amount of data to support its use as an alternative.2 Most reservations for using peramivir stem from a randomized controlled trial that evaluated intravenous peramivir with an institution’s standard of care (SOC) and found no significant clinical benefit in using peramivir with the SOC, compared to SOC alone in hospitalized patients with influenza.13  However, there are additional observational data that have shown that peramivir may be as effective in improving clinical outcomes in hospitalized patients.14-16 Lastly, the use of peramivir as a salvage therapy in patients who failed oseltamivir have also been described. In these critically ill high-risk patients the reported survival rates ranged from 51% to 62%.17,18

Table 2. Antiviral medications for treatment of influenza.2,5,19-22*

Antiviral

FDA-approved uses

Considerations

Neuraminidase inhibitors

Oseltamivir, oral

Treatment of acute, uncomplicated influenza A and B in patients ≥2 weeks of age who have been symptomatic for ≤48 hours

Prophylaxis of influenza A and B in patients ≥1 year of age

  • Preferred agent for hospitalized patients
  • Preferred agent in pregnancy
  • Can be given to all pediatric age groups (data are available to inform some dosing recommendations for neonates and premature infants; see guideline for detail)
  • High-dose strategies should not be routinely used in the treatment of critically ill patients.

Peramivir, intravenous

Treatment of acute, uncomplicated influenza A and B in patients ≥2 years of age who have been symptomatic for ≤48 hours

  • Can be considered in hospitalized patients who are unable to tolerate or absorb oral or enterically-administered oseltamivir

Zanamivir, inhaled

Treatment of acute, uncomplicated influenza A and B in patients ≥7 years of age who have been symptomatic for ≤48 hours

Prophylaxis of influenza A and B in patients ≥5 year of age

  • Not recommended for hospitalized patients due to a lack of data
  • Not recommended in patients with underlying respiratory conditions
  • Considered to be the preferred agent in pregnancy when used for chemoprophylaxis due to its low blood serum concentrations with inhaled administration

Other agents

Baloxavir, oral

Treatment of acute, uncomplicated influenza A and B in patients ≥12 years of age who have been symptomatic for ≤48 hours

  • Recently approved; data are limited to use in uncomplicated influenza
  • Not included in the IDSA recommendations due to its approval after finalization of the guideline

  * Amantadine and rimantadine are also FDA-approved for the treatment of influenza A, but they are currently not recommended by the IDSA or CDC due to high rates of resistance.2,5

Institutional outbreak control

The IDSA recommends that outbreak control measures should be initiated once there are 2 cases of healthcare-associated influenza identified within 72 hours of each other in patients of the same ward or unit in hospitals and long-term care facilities.2 Control measures should include identifying any patients with acute respiratory symptoms, so they can be tested for influenza. Additionally, empiric antiviral therapy can be started as soon as possible in anyone with suspected influenza without waiting for influenza testing results. Other control measures that can be instituted include implementing contact and droplet precautions, minimizing visitors to the unit, and administering antiviral chemoprophylaxis to asymptomatic, exposed patients. More detailed recommendations, including those directed to long-term care facilities, can be found in the IDSA guideline.

Conclusion

The sensitivity and specificity of influenza testing is dependent on the current background incidence of influenza (i.e., the pretest probability), therefore, recommendations for testing vary based on the severity of illness and a patient’s baseline risk of complications.2 Reverse-transcription polymerase chain reaction (RT-PCR) or other molecular assays are recommended for hospitalized patients. Rapid influenza diagnostic tests (RIDTs) should be limited to the outpatient, point-of-care setting. For patients who qualify for antiviral treatment, oseltamivir is the preferred agent, especially in hospitalized patients based on available evidence. The current IDSA guideline recommends that oseltamivir should not routinely be given in higher doses.  Additional information on treatment considerations, including duration of therapy and use of adjunctive agents, management strategies in patients who clinically deteriorate on antiviral therapy, and chemoprophylaxis recommendations can also be found in the IDSA guideline and the reader is directed to the guideline for further information.

References

  1. Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths in the United States — 2017–2018 influenza season. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/about/burden/2017-2018.htm. Updated December 18, 2018. Accessed January 28, 2019.
  2. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza [published online ahead of print December 19, 2018]. Clin Infect Dis. 2018. doi: 10.1093/cid/ciy866.
  3. Information for Clinicians on Influenza Virus Testing. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/professionals/diagnosis/index.htm. Updated February 26, 2018. Accessed January 28, 2019.
  4. People at high risk of developing serious flu-related complications. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/about/disease/high_risk.htm. Updated August 27, 2018. Accessed January 28, 2019.
  5. Influenza antiviral medications: summary for clinicians. Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Updated December 27, 2018. Accessed January 28, 2019.
  6. Noel ZR, Bastin MLT, Montgomery AA, Flannery AH. Comparison of high-dose versus standard dose oseltamivir in critically ill patients with influenza. J Intensive Care Med. 2017;32(10):574-577.
  7. Welch SC, Lam SW, Neuner EA, Bauer SR, Bass SN. High-dose versus standard dose oseltamivir for treatment of severe influenza in adult intensive care unit patients. Intensive Care Med. 2015;41(7):1365-1366.
  8. Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ. 2010;182(4):357-363.
  9. Giraud C, Manceau S, Oualha M, et al. High levels and safety of oseltamivir carboxylate plasma concentrations after nasogastric administration in critically ill children in a pediatric intensive care unit. Antimicrob Agents Chemother. 2011;55(1):433-435.
  10. Mulla H, Peek GJ, Harvey C, Westrope C, Kidy Z, Ramaiah R. Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support. Anaesth Intensive Care. 2013;41(1):66-73.
  11. Eyler RF, Heung M, Pleva M, et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharmacotherapy. 2012;32(12):1061-1069.
  12. Lemaitre F, Luyt CE, Roullet-Renoleau F, et al. Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Ther Drug Monit. 2012 Apr;34(2):171-175.
  13. de Jong MD, Ison MG, Monto AS, et al. Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clin Infect Dis. 2014;59(12):e172-185.
  14. Yoo JW, Choi SH, Huh JW, Lim CM, Koh Y, Hong SB. Peramivir is as effective as oral oseltamivir in the treatment of severe seasonal influenza. J Med Virol. 2015 Oct;87(10):1649-55.
  15. Ison MG, Fraiz J, Heller B, et al. Intravenous peramivir for treatment of influenza in hospitalized patients. Antivir Ther. 2014;19(4):349-361.
  16. Ison MG, Hui DS, Clezy K, et al. A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. Antivir Ther. 2013;18(5):651-661.
  17. Yeh CY, Wang FD, Chuang YC, et al. Clinical outcomes and prognostic factors of patients with severe influenza receiving intravenous peramivir salvage therapy in intensive care units. J Microbiol Immunol Infect. 2018 Dec;51(6):697-704.
  18. Louie JK, Yang S, Yen C, Acosta M, Schechter R, Uyeki TM. Use of intravenous peramivir for treatment of severe influenza A(H1N1)pdm09. PLoS One. 2012;7(6):e40261.
  19. Tamiflu [package insert]. South San Francisco, CA: Genentech, Inc; 2018.
  20. Rapivab [package insert]. Durham, NC: BioCryst Pharmaceuticals, Inc; 2017.
  21. Relenza [package insert]. Research Triangle Park: GlaxoSmithKline; 2018.
  22. Xofluza [package insert]. South San Francisco, CA: Genentech, Inc; 2018.

Prepared by:

Samantha Spencer, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

February 2019

The information presented is current as of January 28, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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