Cases & Commentaries
A Potent Medication Administered in a Not So Viable Route
A 55-year-old man with history of nonischemic cardiomyopathy and severe systolic dysfunction, as well as diffuse atherosclerotic vascular disease, was brought to the emergency department for septic shock of possible intra-abdominal origin. Owing to his cardiac condition, he was given a minimal fluid challenge and vasopressor support was ordered.
The plan was to start norepinephrine bitartrate after the placement of a central intravenous line. However, for reasons that are unclear, the norepinephrine was infused through a peripheral line. It was started at a low dose but then titrated up to 20 μg/hr to address the patient's continued hypotension. Approximately 7 hours later, when the intensive care unit team arrived to transfer the patient to the critical care unit, they were surprised to not find any central line. Instead, they found the norepinephrine was infusing in the peripheral line placed near the patient's right wrist.
The patient now complained of severe pain. However, given his altered mental status in the setting of sepsis, he could not point out where he felt the pain. His right arm, and particularly the fingers, had a bluish discoloration. The team recognized that the vasopressor had extravasated into the subcutaneous tissue of the arm. A right internal jugular line was immediately placed, and the norepinephrine switched to infuse through this central line. Attempts were made to treat the extravasation and salvage the right wrist and fingers, but eventually three of the patient's fingertips had to be amputated. The patient eventually recovered from his sepsis and was discharged home.
The case was discussed in the multi-departmental morbidity and mortality review, and a new protocol was issued that potent medications may be started only after the pharmacy, primary medical team, and nurses identify the medication, route of administration, and plan for titration. The protocol also stated that vasopressors may only be infused through central lines.
by Osama Loubani, MD
The above case illustrates a difficult choice faced by clinicians when caring for patients with shock resistant to fluid resuscitation: (i) Do I start vasopressors through the available peripheral IVs and risk local ischemic complications? Or (ii) do I administer vasopressors only through a central line (thus necessitating emergent insertion of a central line while the patient is in shock and compelling me to tolerate hypoperfusion for whatever time period it takes to insert the central line and confirm its placement)?
The consequences in either case—local tissue injury with the use of peripheral vasopressors, or prolonged hypoperfusion in the case of waiting for a central line—can be significant. When things go badly, clinicians may later be asked what they were thinking by starting vasopressors peripherally, or, alternatively, why they allowed the patient's blood pressure to fall so low for so long. The following discussion is based on the available published evidence and aims to help clinicians in this situation make a decision that balances risks and benefits.
Use of vasopressors to raise blood pressure and improve perfusion in fluid refractory shock is considered standard of care (1), with vasopressors generally titrated to achieve a mean arterial pressure of 65 mm Hg or greater. Vasopressor medications achieve their desired effects on blood pressure through powerful vasoconstriction. This vasoconstriction, if too great, can lead to tissue ischemia and injury. Tissue ischemia and injury are more likely when tissue is exposed to a high concentration of vasopressor, such as when vasopressor doses are very high.
Therefore, administration of vasopressors through central venous catheters is recommended, as the infusion into a central vein dilutes the vasopressor in a large volume of blood, making local complications less likely. However, patients presenting to the emergency department in shock and most inpatients who develop shock typically do not have central lines. As such, a decision to require a central line means that one must be inserted emergently in these unstable patients to allow for vasopressor administration. This procedure takes precious time during which the patient remains hypoperfused. Further, central line insertion during emergency situations are more likely to be associated with complications than when they are inserted under more stable conditions.(2)
This brings us back to our central question: do we tolerate hypoperfusion until a central line is inserted, or do we start vasopressors peripherally and accept the risk of local complications? As the harms of hypoperfusion are significant and well understood, the real question becomes: what are the risks of peripheral IV administration of vasopressor?
A colleague and I recently published a systematic review of tissue injury local to vasopressor infusion in peripheral IVs.(3) Between 1946–2014, we identified 204 published cases of local tissue injury events from peripheral administration of vasopressors. Of these, the majority occurred when vasopressors were given for a very long duration (55.9 ± 68.1 hours), and in a distal body part (e.g., hands, feet). Complications were seldom seen in peripheral infusions given for short durations in proximal areas such as the antecubital fossa or arm. The case above, where ischemia was observed after a 7-hour infusion of vasopressor into an IV placed in the patient's wrist, fits this general pattern of a relatively prolonged infusion in a distal site.
Although our study focused on the length of the infusion, other evidence points to the relative safety of peripheral administration of vasopressors. In a single-center observational study done in Long Island, 734 patients received vasopressor medications through peripheral IVs for an average of 49 hours (± 22 hours).(4) While 2% of patients experienced vasopressor extravasation, no tissue injuries were reported. Perhaps the most important aspect of this study was the rigorous requirements that had been established for the use of peripheral IVs for the administration of vasopressors in the study hospital. These requirements included, among other things, a vein diameter greater than 4 mm measured with ultrasonography, blood return from the IV prior to vasopressor administration, and regular assessment of the peripheral IV site.
Based on this literature, it seems unlikely that peripheral administration of vasopressors will cause serious local complications if IVs are of good quality, in a proximal location, and the duration of infusion is minimized. As such, our center's practice is to allow the use of peripheral vasopressor administration for no more than 2 hours, and only when a good quality peripheral IV is in place in a proximal area (antecubital fossa or more proximal). The 2-hour limit was chosen because very few published cases of local tissue injury events occurred within this time frame—of 138 published cases of local tissue injury where the duration of infusion was given, only 4 occurred within 2 hours. Another consideration that went into this decision was our concern that recommending longer durations could result in a complacency that would prevent clinicians from inserting central lines in an expeditious manner. A national position statement (5) published by the Canadian Association of Emergency Physicians endorses the use of peripheral vasopressor administration for up to 2 hours.
Clinicians can therefore use peripheral vasopressors to rapidly stabilize the patient in shock. The intraosseous route can also provide rapid access when peripheral IVs are not available.(6) Once hemodynamic stability is achieved, the insertion of a central line can be performed in a more measured manner and in a calm environment.
A complete ban on the use of peripheral vasopressor infusion, as was done by the hospital in response to this case, seems unwarranted based on the available evidence, although it is an understandable reaction to such a severe complication. Rather, the best way to balance the risks and benefits of peripheral vasopressor infusion is to establish clear guidelines on the requirements regarding peripheral IV use for administering vasopressors. In particular, such guidelines should address the requirement for proximal location of the IV, the hourly assessment of the site of infusion, and an infusion duration lasting no more than 2 hours.
When using peripheral vasopressors, clinicians should be prepared for the possibility of complications. Regular (e.g., hourly) checks of the infusion site should be performed to inspect for signs of extravasation or other ischemic findings (e.g., mottled skin, discoloration, etc.). However, clinicians should be aware that ischemic complications can occur even in the absence of extravasation.(3) If complications are observed, the vasopressor infusion should be relocated to another area, and vasodilating medications should be used to reverse local vasoconstriction.(7) Vasodilating medications should be administered as soon as possible after tissue complications are detected to restore perfusion and prevent permanent tissue injury. So long as vasopressor-induced vasoconstriction is felt to be causing tissue ischemia, vasodilating medications should be administered; there is no set time beyond which the administration of vasodilating medications is ineffective.
Phentolamine, an alpha antagonist, is commonly used to reverse the vasoconstriction from vasopressors. A 10 mg dose of phentolamine should first be diluted in 10 cc of saline, to give a concentration of 1 mg/mL. Then, 0.5–1 mL of phentolamine should be injected around the edges of the area of extravasation or ischemia, taking care to use a separate needle for each injection. This introduces the phentolamine into the area of extravasation/ischemia, but also punctures the skin to allow fluid extravasated into the tissue to exude. Nitroglycerin paste can also be used on the area of extravasation or ischemia. If skin ischemia progresses to necrosis and tissue death, treatment usually consists of local dressing, debridement, and possibly amputation, depending on the extent of injury.
In summary, when faced with a patient in shock refractory to adequate fluid resuscitation, the administration of vasopressors can be lifesaving. These medications can safely be administered through peripheral IVs if the IV is in a proximal location such as the antecubital fossa, has good blood return, and flushes easily. Such peripheral infusion can allow the rapid stabilization of the patient and facilitate the orderly insertion of a central line in a stable environment. The site of vasopressor infusion should be monitored regularly for signs of complications, and the duration of vasopressor infusion should be kept to no more than 2 hours. If extravasation or ischemic complications occur, they can be treated with administration of phentolamine and nitroglycerine paste to the area.
- Vasopressor medications cause vasoconstriction and have the potential to cause local tissue injury when infused peripherally. A review of reported cases indicates that the risk of local tissue injury with peripheral infusion is highest with long durations of infusion and with infusion in distal sites (e.g., hands, feet).
- Infusion through a central line is ideal. In patients without a central line, insertion can take a long time and waiting for a central line to be inserted may prolong the time the patient is in shock.
- Vasopressor infusion for short durations (< 2 hours) through a proximally sited and well-functioning peripheral IV is unlikely to cause serious local complications. Care should be exercised to avoid prolonging the use of a peripheral IV for vasopressor infusion beyond 2–4 hours or for any length of time in a marginally functioning IV.
- If extravasation does occur, vasodilating agents should be immediately administered to reverse local ischemia, namely phentolamine and nitroglycerin paste.
Osama Loubani, MD Assistant Professor of Medicine Department of Critical Care, Department of Emergency Medicine QEII Health Science Centre Dalhousie University Halifax, Nova Scotia, Canada
1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165-228. [go to PubMed]
2. Ramadan H, Metin Aksu N, Akkas M, Husamettin Akkucuk M, Coskun F, Cetinkaya Sardan Y. Mechanical and infectious complications developing due to central venous catheterizations in the emergency department. Med Glas (Zenica). 2013;10:40-45. [go to PubMed]
3. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015;30:653.e9-653.e17. [go to PubMed]
4. Cardenas-Garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig SJ, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med. 2015;10:581-585. [go to PubMed]
5. Djogovic D, MacDonald S, Wensel A, et al. Vasopressor and inotrope use in Canadian emergency departments: evidence based consensus guidelines. CJEM. 2015;17:1-2. [go to PubMed]
6. Soar J, Nolan JP, Böttiger BW, et al. European Resuscitation Council Guidelines for Resuscitation 2015: Section 3. Adult advanced life support. Resuscitation. 2015;95:100-147. [go to PubMed]
7. Reynolds PM, MacLaren R, Mueller SW, Fish DN, Kiser TH. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy. 2014;34:617-632. [go to PubMed]