Drugs

Should I consider a direct oral anticoagulant (DOAC) for my patient with pancreatic cancer and pulmonary embolism?

FA Manian MD, MPH, , , , , , , , , , , , Leave a comment

Classically, anticoagulant (AC) of choice in active malignancy with venous thromboembolism (VTE) has been low-molecular weight heparin (LMWH) (eg, enoxaparin) because of trials showing its superiority over warfarin. But now the pendulum is swinging toward DOACs as an alternative mode of treatment.

A 2018 trial found that oral edoxaban (an Xa inhibitor) was noninferior to subcutaneous dalteparin (a LMWH) with the composite outcome of recurrent VTE or major bleeding.1 Overall, recurrent VTE was significantly lower in edoxaban (7.9% vs 11.3%) but had higher major bleeding (6.9% vs 4.05). Of note, edoxaban was initiated after 5 days of treatment with LMWH.

More recently, the 2020 Caravaggio trial, showed non-inferiority of apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) to dalteparin with recurrent VTE of 5.6% in the apixaban group vs 7.9% in the dalteparin.2 There was no significant difference in rates of major bleeding (3.8% vs 4%). A prior small study, the ADAM-VTE trial, compared apixaban to dalteparin in patients with malignancy and VTE.3 Apixaban had significantly lower VTE recurrence rates (0.7% to 6.3%) and non-significant lower major bleeding (0% vs 1.4%, p=0.138) consistent with the newer and larger trial. Of note, this trial excluded patients with brain tumor and had few patients with upper GI or hematologic malignancy.  

In addition, a pilot study, the SELECT-D trial, compared rivaroxaban to dalteparin.4 Rivaroxaban had significantly lower VTE recurrence (4% vs 11%), without a significant increase in major bleeding (6% vs 4%), but had an increased number of clinically relevant non-major bleeds (13% vs 4%), particularly in cancers of the upper GI tract.

Although decision regarding use of DOACs in patients with malignancy should be made on case-by-case basis, they are increasingly considered for treatment of VTE in this patient population with the strongest evidence supporting apixaban or the initial use of LMWH for 5 days followed by edoxaban.  

Contributed by Sean Mendez MD, Mass General Hospital, Boston, MA.

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References:  

  1. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. doi: 10.1056/NEJMoa1711948. Epub 2017 Dec 12. PubMed PMID: 29231094.
  2. McBane Ii R, Loprinzi CL, Ashrani A, Perez-Botero J, Leon Ferre RA, Henkin S, Lenz CJ, Le-Rademacher JG, Wysokinski WE. Apixaban and dalteparin in active malignancy associated venous thromboembolism. The ADAM VTE Trial. Thromb Haemost. 2017 Oct 5;117(10):1952-1961. doi: 10.1160/TH17-03-0193. Epub 2017 Aug 24. PubMed PMID: 28837207.
  3. Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman MV, Connors JM, Cohen A, Bauersachs R, Brenner B, Torbicki A, Sueiro MR, Lambert C, Gussoni G, Campanini M, Fontanella A, Vescovo G, Verso M. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020 Mar 29;. doi: 10.1056/NEJMoa1915103. [Epub ahead of print] PubMed PMID: 32223112.
  4. Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. doi: 10.1200/JCO.2018.78.8034. Epub 2018 May 10. PubMed PMID: 29746227.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Should I consider a direct oral anticoagulant (DOAC) for my patient with pancreatic cancer and pulmonary embolism?

Do statins have a role in treating novel Coronavirus infection, COVID-19?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

There is currently no firm clinical evidence that statins improve the outcome of COVID-19. However, there are some theoretical reasons for believing that statins may have a role in the treatment of COVID-19.  That’s because beyond their cholesterol lowering action, statins may also have clinically relevant anti-inflammatory and antiviral (pleotropic) properties.  

Anti-inflammatory: Anti-inflammatory effect of statins is well known and is thought to occur through a variety of molecular pathways of the innate and adaptive immune systems as well as attenuation of several circulating proinflammatory cytokines.1 Although observational studies have suggested that statins lower hospitalization and mortality among outpatients hospitalized with infection, pneumonia or sepsis, several randomized controlled trials (RCTs) have failed to show any mortality benefit among ICU patients with sepsis and ARDS treated with statins.2

In contrast, an RCT involving patients with sepsis (majority with pneumonia, mean CRP 195 mg/dL) reported significant reduction in progression to severe sepsis among statin-naïve patients  placed on atorvastatin 40 mg/day at the time of hospitalization.3 So, perhaps timing of statin therapy before florid sepsis and ARDS is an important factor.  

Some have suggested that statins may decrease the fatality rate of a related Coronavirus, Middle East Respiratory Syndrome (MERS) virus, by blunting exuberant inflammatory response that may result in a fatal outcome. 4

Antiviral: Statins may also have antiviral properties, including activity against influenza, hepatitis C virus, Zika and dengue viruses.2,5 Whether statins have activity against coronaviruses such as the agent of COVID-19 is unclear at this time.

It’s interesting to note that cholesterol may have an important role in the membrane attachment, fusion and replication of many enveloped viruses, including influenza.5 Covid-19 is also an enveloped virus.

So what do we do? Based on the current data, it makes sense to continue statins in patients who have known clinical indications for their use and no obvious contraindications because of COVID-19 (eg. rhabdomyolysis).6 As for statin-naïve patients, particularly those in early stages of sepsis and increased risk of cardiovascular events, benefit may outweigh the risk.  Only proper clinical studies will give us more definitive answers.

Bonus Pearl: Did you know that lipids make up a major component of the envelope in enveloped viruses and that cholesterol makes up nearly one-half of total lipid and over 10% the total mass of influenza viruses?

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References

  1. Tousoulis D, Psarros C, Demosthenous M, et al. Innate and adaptive inflammation as a therapeutic target in vascular diseae: The emerging role of statins. J Am Coll Cardiol 2014;63:2491-2502. https://www.sciencedirect.com/science/article/pii/S0735109714011553?via%3Dihub
  2. Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124618/pdf/atm-04-21-421.pdf
  3. Patel JM, Snaith C, Thickette DR. Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial) Critical Care 2012;16:R231. https://ccforum.biomedcentral.com/track/pdf/10.1186/cc11895
  4. Espano E, Nam JH, Song EJ, et al. Lipophilic statins inhibit Zika virus production in Vero cells. Scientific Reports 2019;9:11461. https://www.nature.com/articles/s41598-019-47956-1
  5. Sun X, Whittaker GR. Role for influenza virus envelope cholesterol in virus entry and infection. J Virol 2003;77:12543-12551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC262566/
  6. Virani SS. Is there a role for statin therapy in acute viral infections. Am Coll Cardiol March 18, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/09/is-there-a-role-for-statin-therapy-in-acute-viral-infections-covid-19

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Do statins have a role in treating novel Coronavirus infection, COVID-19?

What’s causing an isolated GGT elevation in my patient with an abnormal alkaline phosphatase on her routine admission lab?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , Leave a comment

Although serum gamma-glutamyl transpeptidase or GGT is a very sensitive test for liver disease, especially of biliary origin, it’s by no means a very specific test. Besides the liver, GGT is found in the kidneys, pancreas, prostate, heart, brain, and seminal vesicles but not in bone (1-4).

 
Obesity, alcohol consumption and drugs are common causes of GGT elevation (2). As early as 1960s, elevated GGT was reported in such seemingly disparate conditions as diabetes mellitus, congestive heart failure, myocardial infarction, nephrotic syndrome and renal neoplasm (3). Nonalcoholic steatohepatitis, viral hepatitis, biliary obstruction, COPD, liver metastasis, drug-induced liver injury can all cause GGT elevation (1-4).

 
An isolated GGT does not necessarily indicate serious or progressive liver disease. That’s one reason it’s often not included in routine “liver panel” lab tests (1).

What to do when GGT is high but other liver panel tests such as ALT, AST, albumin, and bilirubin are normal? If your patient is at risk of acquired liver disease, then further workup may be necessary (eg, hepatitis B and C screening tests). Alcohol consumption should be queried. Don’t forget conditions associated with iron overload. If your patient is obese, diabetic or has elevated both lipids, an ultrasound of the liver to look for fatty liver should be considered. In the absence of risk factors, symptoms, or physical exam suggestive of liver disease, isolated GGT elevation should not require further investigation (1).

 
One good thing that may come out of finding an isolated elevated GGT is to encourage your patient to curb alcohol consumption or lose weight when indicated. But don’t rely on a normal GGT to rule out heavy alcohol consumption as it may miss 70% to 80% of cases (6)! 

 
Bonus Pearl: Did you know that GGT activity is thought to increase in alcohol use due to its role in maintaining intracellular glutathione, an anti-oxidant, at adequate levels to protect cells from oxidative stress caused by alcohol?

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References

1. Carey WD. How should a patient with an isolated GGT elevation be evaluated? Clev Clin J Med 2000;67:315-16. https://www.ncbi.nlm.nih.gov/pubmed/10832186
2. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut 2018;67:6-19. https://gut.bmj.com/content/gutjnl/67/1/6.full.pdf
3. Whitfield JB, Pounder RE, Neale G, et al. Serum gamma-glutamyl transpeptidase activity in liver disease. Gut 1972;13:702-8. https://www.ncbi.nlm.nih.gov/pubmed/4404786
4. Tekin O, Uraldi C, Isik B, et al. Clinical importance of gamma glutamyltransferase in the Ankara-Pursaklar region of Turkey. Medscape General Medicine 2004;6(1):e16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140713/
5. Van Beek JHDA, de Moor MHM, Geels LM, et al. The association of alcohol intake with gamma-glutamyl transferase (GGT) levels:evidence for correlated genetic effects. Drug Alcohol Depend 2014;134:99-105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909645/

6. Bertholet N, Winter MR, Cheng DM, et al. How accurate are blood (or breath) tests for identifying self-reported heavy drinking among people with alcohol dependence? Alcohol and Alcoholism 2014;49:423-29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060735/pdf/agu016.pdf

What’s causing an isolated GGT elevation in my patient with an abnormal alkaline phosphatase on her routine admission lab?

When can I resume anticoagulation in my patient with atrial fibrillation and hemorrhagic stroke?

FA Manian MD, MPH, , , , , , Leave a comment

Optimal timing of resumption of therapeutic anticoagulation (AC) in patients with hemorrhagic stroke or intracranial hemorrhage (ICH) is unclear because of lack of randomized controlled trials, but existing evidence suggests that 4-8 weeks may be reasonable in our patient (1). 
The American Heart Association/American Stroke Association 2015 guidelines recommend avoiding AC for at least 4 weeks in patients without mechanical heart valves (class IIB-very weak), while 1 study reported that prediction models of ICH in atrial fibrillation at high risk of thromboembolic event suggest that resumption of AC at 7-8 weeks may be the “sweet spot” when weighing safety against efficacy of AC in this patient population (1-3).
Two meta-analyses (1 involving patients with non-lobar ICH, another ICH in patients with nonvalvular atrial fibrillation) found that resumption of AC ranging from 10 to 44 days following ICH may be associated with decrease rates of thromboembolic events without significant change in the rate of repeat ICH (4,5).
There are many limitations to the published literature including their retrospective nature, unreported location and size of ICH in many studies, and use of warfarin (not DOACs) as an AC agent (1).
Clearly we need randomized controlled trials to answer this important question. In the meantime, a heavy dose of clinical judgement on a case-by-case basis seems appropriate.

Bonus Pearl: Did you know that lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) usually due to hypertensive vessel disease (1)? 

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References
1. Gibson D et al. When is it safe to resume anticoagulation in my patient with hemorrhagic stroke. The Hospitalist, February 5, 2019. https://www.the-hospitalist.org/hospitalist/article/193924/neurology/when-it-safe-resume-anticoagulation-my-patient-hemorrhagic/page/0/1
2. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60. https://www.ahajournals.org/doi/pdf/10.1161/STR.0000000000000069
3. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20 https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.116.014643
4. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600. https://www.ahajournals.org/doi/full/10.1161/strokeaha.116.016327
5. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730065/

When can I resume anticoagulation in my patient with atrial fibrillation and hemorrhagic stroke?

Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Short answer: Yes! Although we usually associate acute acalculous cholecystitis (AAC) with critically ill patients (eg, with sepsis, trauma, shock, major burns) in ICUs, AAC is not as rare as we might think in ambulatory patients. In fact, a 7 year study of AAC involving multiple centers reported that AAC among outpatients was increasing in prevalence and accounted for 77% of all cases (1)!

 
Although the pathophysiology of ACC is not fully understood, bile stasis and ischemia of the gallbladder either due to microvascular or macrovascular pathology have been implicated as potential causes (2). One study found that 72% of outpatients who developed ACC had atherosclerotic disease associated with hypertension, coronary, peripheral or cerebral vascular disease, diabetes or congestive heart failure (1). Interestingly, in contrast to calculous cholecystitis, “multiple arterial occlusions” have been observed on pathological examination of the gallbladder in at least some patients with ACC and accordingly a name change to “acute ischemic cholecystitis” has been proposed (3).

 
AAC can also complicate acute mesenteric ischemia and may herald critical ischemia and mesenteric infarction (3). The fact that cystic artery is a terminal branch artery probably doesn’t help and leaves the gallbladder more vulnerable to ischemia when arterial blood flow is compromised irrespective of the cause (4).

 
Of course, besides vascular ischemia there are numerous other causes of ACC, including infectious (eg, viral hepatitis, cytomegalovirus, Epstein-Barr virus, Salmonella, brucellosis, malaria, Rickettsia and enteroviruses), as well as many non-infectious causes such as vasculitides and, more recently, check-point inhibitor toxicity (1,5-8).

 
Bonus Pearl: Did you know that in contrast to cholecystitis associated with gallstones (where females and 4th and 5th decade age groups predominate), ACC in ambulatory patients is generally more common among males and older age groups (mean age 65 y) (1)?

 

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References
1. Savoca PE, Longo WE, Zucker KA, et al. The increasing prevalence of acalculous cholecystitis in outpatients: Result of a 7-year study. Ann Surg 1990;211: 433-37. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1358029/pdf/annsurg00170-0061.pdf
2. Huffman JL, Schenker S. Acute acalculous cholecystitis: A review. Clin Gastroenterol Hepatol 2010;8:15-22. https://www.cghjournal.org/article/S1542-3565(09)00880-5/pdf
3. Hakala T, Nuutinene PJO, Ruokonen ET, et al. Microangiopathy in acute acalculous cholecystitis Br J Surg 1997;84:1249-52. https://bjssjournals.onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2168.1997.02775.x?sid=nlm%3Apubmed
4. Melo R, Pedro LM, Silvestre L, et al. Acute acalculous cholecystitis as a rare manifestation of chronic mesenteric ischemia. A case report. Int J Surg Case Rep 2016;25:207-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941110/
5. Aguilera-Alonso D, Median EVL, Del Rosal T, et al. Acalculous cholecystitis in a pediatric patient with Plasmodium falciparum infection: A case report and literature review. Ped Infect Dis J 2018;37: e43-e45. https://journals.lww.com/pidj/pages/articleviewer.aspx?year=2018&issue=02000&article=00020&type=Fulltext  
6. Kaya S, Eskazan AE, Ay N, et al. Acute acalculous cholecystitis due to viral hepatitis A. Case Rep Infect Dis 2013;Article ID 407182. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784234/pdf/CRIM.ID2013-407182.pdf
7. Simoes AS, Marinhas A, Coelho P, et al. Acalculous acute cholecystitis during the course of an enteroviral infection. BMJ Case Rep 2013;12. https://casereports.bmj.com/content/12/4/e228306
8. Abu-Sbeih H, Tran CN, Ge PS, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J ImmunoTherapy of Cancer 2019;7:118. https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0604-2

 

 

Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

My 65 year old patient on chronic warfarin happens to have diffuse tracheobronchial calcification on her chest X-ray. Could warfarin be the culprit?

FA Manian MD, MPH, , , , , , , , , Leave a comment

Absolutely! Although tracheobronchial calcification (TBC) is often found as part of normal aging process in the elderly, especially women, long-term warfarin use has also been implicated as a cause of TBC, even among those with less advanced age (1-4).

In a cohort of patients 60 years of age or older, radiographic evidence of trachea and bronchi calcification was found in 47% of patients on warfarin (mean age 64 years, mean duration of treatment 6 years) compared to 19% of controls (1). A positive correlation between the duration of warfarin therapy and increased levels of calcification was also found.  Fortunately, TBC is a benign finding and has no health consequences.

As for the mechanism for this rather intriguing phenomenon, the inhibition of a vitamin K-dependent protein that prevents calcification of cartilaginous tissue seems to be the most plausible (1). Although we often think of vitamin-K dependent factors in relation to the coagulation cascade, several vitamin K-dependent proteins also play an important role in the inhibition of calcification in soft tissues and blood vessels (eg, matrix Gla protein-MGP) (5,6).

In fact, rats maintained on warfarin undergo calcification of cartilage and elastic connective tissue, while exposure of the fetus to warfarin during pregnancy is associated with calcifications in and around joints, airway and nasal cartilages (4,7). These observations further support a causative role of warfarin in inducing TBC.

 

Bonus Pearl: Did you know that MGP deficiency in humans is known as the Keutel syndrome, a rare autosomal recessive disease characterized by several characteristic physical features, including severe cartilage calcifications and depressed nasal bridge?

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References

  1. Moncada RM, Venta LA, Venta ER, et al. Tracheal and bronchial cartilaginous rings: warfarin sodium-induced calcification. Radiology 1992;184:437-39. https://pubs.rsna.org/doi/10.1148/radiology.184.2.1620843
  2. Thoongsuwan N, Stern EJ. Warfarin-induced tracheobronchial calcification. J thoracic Imaging 2003;18:110-12. https://journals.lww.com/thoracicimaging/Abstract/2003/04000/Warfarin_Induced_Tracheobronchial_Calcification.12.aspx
  3. Nour SA, Nour HA, Mehta J, et al. Tracheobronchial calcification due to warfarin therapy. Am J Respir Crit Care Med 2014;189:e73. https://www.atsjournals.org/doi/full/10.1164/rccm.201305-0975IM
  4. Joshi A, Berdon WE, Ruzal-Shapiro C, et al. CT detection of the tracheobronchial calcification in an 18 year-old on maintenance warfarin sodium therapy. AJR Am J Roentgenol 2000;175:921-22. https://www.ajronline.org/doi/full/10.2214/ajr.175.3.1750921
  5. Wen L, Chen J, Duan L, et al. Vitamin K-dependent proteins involved in bone and cardiovascular health (review). Molecular Medicine Reports 2018;18:3-15. https://www.spandidos-publications.com/mmr/18/1/3/abstract \
  6. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr 2012; 3:166-173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648717/pdf/166.pdf

7.      Price PA, Williamson MK, Haba T, et al. Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc Natl Acad Sci  U.S.A 1982;79:7734-8. https://www.ncbi.nlm.nih.gov/pubmed/6984192

My 65 year old patient on chronic warfarin happens to have diffuse tracheobronchial calcification on her chest X-ray. Could warfarin be the culprit?

My patient with chronic pain complains of difficulty sleeping. Would improving her sleep hygiene impact her pain medication requirement?

FA Manian MD, MPH, , , , , Leave a comment

Most likely!

We should routinely assess for poor sleep as a potential impediment to adequate pain control in our patients. Substantial research supports a bidirectional relationship between pain and sleep.  That is, not only can pain disrupt sleep but sleep quality can also adversely affect pain.1   In fact, even a short-term disturbance in a stable sleep pattern may lower the pain threshold 2 and the ability to tolerate previously controlled pain.3

These observations are thought to result from activated stress responses from poor sleep hygiene which in turn produce cellular oxidative stress and inflammation of tissues and the nervous system. 4 This process can result in a vicious cycle between increasing pain and persistent insomnia.4,5  Breaking this cycle can reduce pain and improve function, among other desired outcomes.

Ongoing insomnia may also be a sign of a variety of other conditions that should be treated, such as mood disorder and sleep apnea. For example, besides standard non-pharmaceutical measures to improve sleep hygiene, continuous positive air pressure (CPAP) can reduce pain and opioid use in the setting of sleep apnea .2,6

Remember also that controlling pain with opioids in hopes of improving sleep may be counterproductive as opioids can contribute to sleep apnea.7,8  Melatonin may be a better sleep aid in this setting. 9

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References

  1. Wei Y, Blanken TF, Van Someren EJW. Insomnia really hurts: effect of a bad night’s sleep on pain increases with insomnia severity. Front Psychiatry 2018;9:377. doi: 10.3389/fpsyt.2018.00377. https://www.ncbi.nlm.nih.gov/pubmed/30210367
  2. Charokopos A, Card ME, Gunderson C, Steffens C, Bastian LA. The association of obstructive sleep apnea and pain outcomes in adults: a systematic review. Pain Med 2018;19(suppl_1):S69-S75. doi: 10.1093/pm/pny140. https://www.ncbi.nlm.nih.gov/pubmed/30203008
  3. Sivertsen B, Lallukka T, Petrie KJ, et al. Sleep and pain sensitivity in adults. Pain. 2015;156:1433-9. https://www.ncbi.nlm.nih.gov/pubmed/25915149
  4. Iacovides S, George K, Kamerman P, Baker FC. Sleep fragmentation hypersensitizes healthy young women to deep and superficial experimental pain. J Pain. 2017;18:844-854. doi: https://doi.org/10.1016/j.jpain.2017.02.436. https://www.ncbi.nlm.nih.gov/pubmed/28300651
  5. Edwards RR, Almeida DM, Klick B, Haythornthwaite JA, Smith MT. Duration of sleep contributes to next-day pain report in the general population. Pain. 2008;137:202-7. doi: 10.1016/j.pain.2008.01.025. https://www.ncbi.nlm.nih.gov/pubmed/18434020
  6. Edwards RR, Almeida DM, Klick B, Haythornthwaite JA, Smith MT. Duration of sleep contributes to next-day pain report in the general population. Pain. 2008 Jul;137(1):202-7. doi: 10.1016/j.pain.2008.01.025. https://www.ncbi.nlm.nih.gov/pubmed/18434020
  7. Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. Prog Neuropsychopharmacol Biol Psychiatry 2018 20;87:234-244. https://www.ncbi.nlm.nih.gov/pubmed/28734941
  8. Jungquist CR, Flannery M, Perlis ML, Grace JT. Relationship of chronic pain and opioid use with respiratory disturbance during sleep. Pain Manag Nurs 2012;13:70-9. doi: 10.1016/j.pmn.2010.04.003. https://www.ncbi.nlm.nih.gov/pubmed/22652280
  9. Landis CA. Is melatonin the next “new” therapy to improve sleep and reduce pain? Sleep 2014; 37: 1405–1406. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153056/

Contributed by Paul Arnstein, PhD, RN, FAAN, Mass General Hospital, Boston, MA.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

My patient with chronic pain complains of difficulty sleeping. Would improving her sleep hygiene impact her pain medication requirement?

Why is latent tuberculosis usually treated with one antibiotic while active tuberculosis is treated with 2 or more drugs?

FA Manian MD, MPH, , , , , , , Leave a comment

Conventional wisdom has been that in active tuberculosis (TB) patients harbor large numbers of replicating Mycobacterium tuberculosis (Mtb), requiring multiple antibiotics to prevent the emergence of resistant mutants. In contrast, Mtb under latent or “inactive” conditions is presumed to have little capacity for mutation due to reduced bacterial replication, thus generally requiring only one antibiotic for preventive therapy.1

However, the assumption that Mtb has a low capacity for mutation in latent TB due to slow bacterial replication has been challenged in recent years. An experimental study in macaque monkeys with latent Mtb infection using whole genome sequencing demonstrated that despite reduced replication, Mtb acquires a similar number of chromosomal mutations during latency as it does during active infection.1

This finding supports the more current and evolving concept of latent TB which assumes diverse mycobacterial growth states, ranging from complete absence of organisms to actively replicating bacterial populations.2 It also explains why, although effective, isoniazid monotherapy may be a risk factor for the emergence of INH resistance in latent TB. 1,3

 Bonus Pearl: Did you know that INH treatment of latent TB in adults is 60-80% protective when given for 6 months, and 90% protective when given for 9 months? 4

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References

  1. Ford CB, Lin PL, Chase M, et al . Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet. 2011;43:482-86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101871/
  2. Gideon HP, Flynn JL. Latent tuberculosis: what the host “sees”? Immunol Res 2011;50:202-12. https://www.ncbi.nlm.nih.gov/pubmed/21717066
  3. Balcells ME, Thomas SL, Faussett PG, et al. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744-51. https://www.ncbi.nlm.nih.gov/pubmed/16704830
  4. Piccini P, Chiappini E, Tortoli E, et al. Clinical peculiarities of tuberculosis. BMC Infect Dis 2014; 14 (Suppl 1):S4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015485/

 

Why is latent tuberculosis usually treated with one antibiotic while active tuberculosis is treated with 2 or more drugs?

Is neurotoxicity caused by cefepime common?

FA Manian MD, MPH, , , , , , , , , Leave a comment

The incidence of cefepime-induced neurotoxicity (CIN) has varied from 1% to 15%.1 Potential clinical manifestations of CIN include delirium, impaired level of consciousness, disorientation/agitation, myoclonus, non-convulsive status epilepticus, seizures, and aphasia.1  Many of these signs and symptoms (eg, delirium) are common among hospitalized patients.

Although renal dysfunction and inadequately adjusted dosages are often cited as risk factors, one-half of patients develop suspected CIN despite apparently proper adjustment for renal function.1  In addition,  several case reports of CIN have involved patients with normal renal function. 2  A study of 1120 patients receiving cefepime found epileptiform discharges in 14 cases, most having normal renal function.3 Of interest, in the same study, the prevalence of epileptiform discharges was 6-fold higher than that of meropenem!

Proposed mechanisms for CIN include its avidity for central nervous system GABA-A receptors (higher than that of many beta-lactam antibiotics) combined with its high concentration in brain tissue.1 Renal impairment, decreased protein binding, and increased organic acid accumulation can increase transfer of cefepime across the blood brain barrier from an expected 10% to up to 45% of its serum concentration, further contributing to its neurotoxicity.4

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 References

 

  1. Appa AA, Jain R, Rakita RM, et al. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infectious Diseases 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170. eCollection 2017 Fall. https://www.ncbi.nlm.nih.gov/pubmed/29071284
  2. Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxford Medical Case Reports, 2016;6, 118-120. https://academic.oup.com/omcr/article/2016/6/118/2362353
  3. Naeije G, Lorent S, Vincent JL, et al. Continuous epileptiform discharges in patients treated with cefpime or meropenem Arch Neurol 2011;68:1303-7. https://www.ncbi.nlm.nih.gov/pubmed/21987544
  4. Payne LE, Gaganon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Critical Care 017;21:276. https://www.ncbi.nlm.nih.gov/pubmed/29137682

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

Is neurotoxicity caused by cefepime common?

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

The most helpful lab data favoring corticosteroid-induced granulocytosis (CIG) is the absence of a shift to the left in the peripheral WBC (ie, no more than 6% band forms) and toxic granulation.1 Although the total WBC itself is less helpful, experimental studies have reported a mean maximum neutrophil counts 2.4 times the base line after IV injection of hydrocortisone (200 mg) 2, and a mean increase of 4,000 neutrophils/mm3 after prednisone (20-80 mg). 3

Several possible mechanisms for CIG revolving around altered neutrophil characteristics and dynamics have been proposed4, including

  • Reduced egress from blood into tissues
  • Demargination from vascular endothelial surfaces
  • Delayed apoptosis
  • Enhanced release from the bone marrow.

An experimental animal study reported that only 10% of CIG is related to bone marrow release of neutrophils with the rest related to demargination (61%) and reduced egress from blood or delayed apoptosis (29%).4 This study may explain why high percentage of band forms would not be expected in CIG.

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References

  1. Shoenfeld Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis: influence of dosage, method, and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-78. Link
  2. Bishop CR, Athens JW, Boggs DR, et al. Leukokinetic studies: A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1986;47:249-60. https://www.ncbi.nlm.nih.gov/pubmed/5638121
  3. Dale DC, Fauci AS, Guerry DuPont, et al. Comparison of agents producing a neutrophilic leukocytosis in man. J Clin Invest 1975;56:808-13. PDF
  4. Nakagawa M, Terashma T, D’yachkova YD, et al. Glucocorticoid-induced granulocytosis: Contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998;98:2307-13. PDF

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?