Managing Drug Shortages in the ICU - Thinking Outside the Box

2015 - 4 August – Post-Intensive Care Syndrome
Anthony Gerlach, PharmD, BCPS, FCCP, FCCM; Stacey Folse, PharmD, MPH, BCPS; Farooq Bandali, PharmD
Three experts discuss alternative treatment options during drug shortages as they relate to electrolytes, vasopressor-induced extravasation, and methemoglobinemia.

 

The Society of Critical Care Medicine’s Drug Shortages Committee is a multiprofessional group charged with providing resources to members to help optimally manage drug shortages affecting critically ill and injured patients. Committee members share their personal experiences, identify current trends in drug shortages and offer insight into various safety and quality improvement issues. Members also provide information on the safe and consistent management of drug shortages as well as on additional resources and strategies in regular Drug Shortage Alerts, which are accessible at www.sccm.org/currentissues.​

Drug shortages are becoming a common occurrence throughout the healthcare spectrum in the United States and affect every phase of care.(1,2) Ongoing drug shortages increased from 150 in 2010 to almost 300 in 2012 and stayed at this level throughout 2014.2 Generic injectable products, such as opiates, antibiotics, electrolytes, heparin, and saline fluids, have been most vulnerable.(1) Furthermore, many agents, both injectable and oral, have been withdrawn from the market; these include phentolamine and sodium biphosphate/sodium phosphate (Fleet Phospho-soda). Unfortunately, there are no easy solutions, especially for patients who are allowed nothing by mouth.

The risks of drug shortages have largely been anecdotal, but intensive care unit (ICU) patients may be at greatest risk. In a recent study of patients receiving parenteral nutrition after laparotomy, Bible et al demonstrated that patients receiving parenteral nutrition during severe shortages required more magnesium supplementation and had longer hospital lengths of stay and more laboratory draws.(1) Similarly, ICU patients who are not able to take oral dosage forms may be at risk for adverse events due to drug shortages. 
 
Electrolytes
Electrolytes are some of the most commonly used medications, and many ICUs use nurse-driven electrolyte replacement protocols. For patients who are mechanically ventilated and have small-bore feeding tubes in place, intravenous (IV) electrolyte replacement may be preferred for a variety of reasons, including the potential for clogging feeding tubes. For example, administration of sodium chloride tablets through a feeding tube is problematic because the tablets do not crush or go into solution easily. Because sodium chloride is readily soluble in water, use of table salts such as salt packets may be an alternative. Six salt packets are approximately equal to one teaspoon or 100 mEq.(3) These dissolve easily in water and can be safely administered through enteral tubes. With the market withdrawal of sodium biphosphate and sodium phosphate solutions, phosphorus replacement is also problematic, because the commercially available tablets do not dissolve easily. Milk may be an alternative. Eight ounces of skim milk contains 8 mmol phosphorus, 5 mEq potassium and 3 mEq sodium.(3)
 
Vasopressor-Induced Extravasation
In critically ill patients, the IV route is usually preferred because of both rapid onset and inability to administer medications orally. However, one of the most serious complications of administering medications intravenously is extravasation injury. These injuries may manifest across a wide spectrum of symptoms, including but not limited to pain, limitations in mobility, nerve damage, loss of limb or limb function, and death.(4) Although cytotoxic agents are most commonly implicated, Le and Patel discovered that during the past 50 years there have been 232 published cases of extravasation injury associated with approximately 37 noncytotoxic agents.(5) Of these, phenytoin, parenteral nutrition, electrolytes, and vasopressors are the most common agents or medication classes. For a comprehensive review of the evaluation and management of extravasation injury secondary to noncytotoxic medications, the reader is referred to two recently published reviews.(5,6)

The true incidence of vasopressor-induced extravasation necrosis is unknown, but earlier data suggest rates as high as 60% and 68% for norepinephrine and dopamine, respectively.(5,6) Phentolamine was the preferred agent in managing vasopressor-induced extravasation injury, but is no longer available. Therefore, clinicians are forced to look for alternatives. Two possible alternatives are terbutaline and topical nitroglycerin. Data are sparse and based on case reports. Terbutaline may be used for extravasation injuries from norepinephrine, epinephrine, dopamine, and dobutamine.(5,6) Topical nitroglycerin is preferred for injuries from vasopressin or methylene blue, but may be used in all vasopressor-induced extravasation injuries.(5,6) Hyaluronidase monotherapy and ice packs should be avoided because these therapies may not be beneficial, and the use of ice packs may even worsen the condition.(6) Table 1 (5,6 )provides a summary of the mechanisms of damage, pharmacologic treatments (including doses), and alternate treatments (including nonpharmacologic treatments).
 
Methemoglobinemia
Acquired methemoglobinemia is a life-threatening complication associated with the administration of some medications (e.g., benzocaine, dapsone, lidocaine, metoclopramide, nitroglycerin, nitroprusside, primaquine, and sulfonamides) commonly used in the ICU. When oxygen delivery is impaired due to methemoglobinemia, methylene blue is the treatment of choice.(7) Currently, methylene blue is on shortage due to manufacturing delays. However, ascorbic acid is an alternate antidote.(7-9) It acts as a strong reducing agent of the methemoglobin molecule in vitro.(9-11) Recent studies and case reports have shown ascorbic acid to be an effective and safe treatment. In these studies, ascorbic acid was given in different doses and durations (1 to 2 grams IV daily for 3 to 4 days and up to 10 grams IV over 6 hours).(7,8,11-13) There is no consensus regarding the dose and duration of ascorbic acid therapy for methemoglobinemia. However, low doses and a short duration of therapy can cause suboptimal reduction in methemoglobin.(10,11) The IV route of administration is preferred, because the oral route cannot attain high serum ascorbic acid concentrations.(11-14) One potential complication of ascorbic acid therapy is an increase in urinary excretion of oxalate.(11-14) In patients with renal insufficiency, long-term administration of high-dose IV ascorbic acid can cause oxalate nephropathy.(6,9) Therefore, renal function should be assessed both before and after treatment, and IV ascorbic acid should be administered for a short duration.   
 

Drug shortages and market withdrawal of injectable medications continue to be problems. Clinicians may need to think outside the box to deal with shortages. Use of alternate and non-traditional products may be options for critically ill patients, especially those who cannot tolerate traditional oral dosage forms. Shortages are best addressed at the level of each institution, through an interdisciplinary team. Having the ICU care team develop and communicate plans to address shortages is essential.

 

References

1. Bible JR, Evans DC, Payne B, Mostafavifar L. Impact of drug shortages on patients receiving parenteral nutrition after laparotomy. JPEN J Parenter Enteral Nutr. 2014 Nov;38(2 Suppl):65S-71S.
2. Furlow B. Persistent drug shortages jeopardise patient safety in the USA. Lancet Respir Med. 2015 Mar;3(3):182-183.
3. Lagua RT, Claudio VS. Nutrition and Diet Therapy Reference Dictionary. New York, NY: Chapman and Hall; 1996.
4.  Upton J, Mulliken JB, Murray JE. Major intravenous extravasation injuries. Am J Surg. 1979 Apr; 137(4):497-506.
5. Le A, Patel S. Extravasation of noncytotoxic drugs: a review of the literature. Ann Pharmacother. 2014 Apr; 48(7):870-886.
6.  Reynolds PM, MacLaren R, Mueller SW, Fish DN, Kiser TH. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy. 2014 Jun;34(6):617-632.
7. Nascimento TS, Pereira RO, de Mello HL, Costa J. Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol. 2008 Nov-Dec:58(6):651-664.
8. Topal H, Topal Y. Toxic methemoglobinemia treated with ascorbic acid: case report. Iran Red Crescent Med J. 2013 Dec;15(12):e12718.
9. Rino PB, Scolnik D, Fustiñana A, Mitelpunkt A, Glatstein M. Ascorbic acid for the treatment of methemoglobinemia: the experience of a large tertiary care pediatric hospital. Am J Ther. 2014 Jul-Aug;21(4):240-243.
10. Park SY, Lee KW, Kang TS. High-dose vitamin C management in dapsone-induced methemoglobinemia. Am J Emerg Med. 2014 Jun;32(6):684.e1-684.e3.
11. Toker I, Yesilaras M, Caliskan Tur F, Toktas R. Methemoglobinemia caused by dapsone overdose: which treatment is best? Turk J Emerg Med. Published online February 17, 2015.
12. Dötsch J, Demirakça S, Cryer A, Hänze J, Kühl PG, Rascher W. Reduction of NO-induced methemoglobinemia requires extremely high doses of ascorbic acid in vitro. Intensive Care Med. 1998 Jun;24(6):612-615.
13. Aydogan M, Toprak DG, Turker G, et al. Intravenous ascorbic acid treatment in prilocaine-induced methemoglobinemia: report of two cases. Turk J Pediatr. 2005;48:65-68.
14 Lee KW, Park SY. High dose vitamin C as treatment of methemoglobinemia. Am J Emerg Med. 2014 Aug:32(8):936.