REBEL Cast Ep73: Are Peripheral Vasopressors Safe?

Background: Traditionally, vasopressors have been given through central venous catheters (CVCs) in the critically ill.However, the time it takes to place a CVC is time a patient could potentially remain hypotensive. Early initiation of vasopressors may be associated with reduced mortality by increasing end-organ perfusion. Therefore, there has been a growing trend to use vasopressors through peripheral IVs (PIVs).  Running pressors through a peripheral IV has a couple of important benefits including faster time to pressor initiation and no need for invasive procedures (i.e. CVC). There islittle evidence to support the safety of this practice other than one systematic review which included case reports and small case series. Now we have two more papers that evaluate this very question…are peripheral pressors safe?

REBEL Cast Episode 73: Are Peripheral Vasopressors Safe?

Tian DH et al 2019 [1]

What They Did:

• Systematic review evaluating the safety of delivering vasopressor medications via PIVs
• Performed a literature search of prospective and retrospective studies of vasopressor infusions in adults

Outcomes:

• Primary: Adverse events related to the use of peripheral vasopressors (i.e. extravasation, skin necrosis, limb ischemia, compartment syndrome, infection, and any other reported complications that required treatment)
• Secondary:
  • Details of administration protocols, policies, and guidelines regarding the management of the infusion (i.e. frequency of observation) 

Inclusion:

• Randomized clinical trials
• Prospective and retrospective cohort trials
• Case series that included at least 20 participants
• Continuous infusions of vasopressor medications (noradrenaline, adrenaline, metaraminol, phenylephrine, dopamine, and vasopressin) delivered via a PIV that included at least 20 patients and reported incidence of adverse events

Exclusion:

• Studies with <20 participants
• Studies using peripherally inserted central catheters (PICC)
• Patients not in shock (i.e. laboratory studies, cardiac arrest, use of push-dose vasopressors or intraoperative use of vasopressors)
• Non-English language
• Review articles

Results:

• 7 studies identified including 1382 patients and 1436 episodes of peripheral vasopressor administration
  • Studies published between 2009 – 2018
  • Number of patients per study ranged between 20 – 734
  • Most catheters were either 18 or 20g in size (Due to low event rate, association between complications and PIV size could not be reliably assessed)
• Most commonly administered agents:
  • Noradrenaline: n = 702 episodes
  • Phenylephrine: n = 546 episodes
  • Dopamine: n = 108 episodes
  • Metaraminol: n = 74 episodes
  • Vasopressin & Adrenaline: < 5 patients
• Mean duration of infusion = 22h (95% CI 8 – 36hrs)
• Extravasation events* = 35 events = 3.4% (95% CI 2.5 – 4.7%)
  • No reported episodes of tissue necrosis or limb ischemia
  • All extravasation events were managed conservatively or with vasodilatory medications

*Looking at table 3 of the paper there were 38, not 35 extravasation events out of 1434, not 1436 infusions, which equals an extravasation rate of 2.6%, NOT 3.4%

Strengths:           

• Predefined inclusion criteria to provide an estimate of the incidence of adverse events associated with the use of vasopressors via a peripheral catheter
• Extensive search strategy ensuring a low chance of missing studies

Limitations:

• All included studies were observational or case series without comparison groups (i.e. no RCTs)
• Paucity of studies examine the use of peripheral vasopressors
• Duration of vasopressor use in the included studies is relatively limited with all but two studies receiving <24hrs of infusion. Therefore, we are unable to draw conclusions regarding the safety of more prolonged infusions
• Variations in the dose and concentrations of vasopressors, variation in the sites and gauge size of peripheral catheters, and monitoring protocols preclude definitive recommendations regarding what constitutes safe medical practice
• 6 of 7 studies were single center
• 5 of 7 studies were unclear regarding consecutiveness of patient inclusion
• 3 of 7 studies did not report competing interests
• Scarcity of primary outcomes precluded sub-group analysis of higher-quality studies
• Only 4 of 7 studies detailed their protocols for peripheral IV insertion

Discussion:

• This study makes it reassuring that the rate of extravasation events is low with the use of peripheral vasopressors, with the caveat that the quality of studies included are not that great.
• It is important to remember that the use of peripheral vasopressors is a bridge to something else and not prolonged infusions. This would either mean the patient improves and comes off vasopressors or does not improve in which case a CVC should be placed.

Author Conclusion: “Reports of the administration of vasopressors via PiVCs, when given for a limited duration, under close observation, suggest that extravasation is uncommon and is unlikely to lead to major complications.”

Clinical Take Home Point: There is clearly a need for further high-quality research in this area. Until that time, the practice of peripheral vasopressors appears to make pragmatic sense to help expedite time to vasopressor infusions. If using this practice, there should be clinical monitoring protocols and protocols for management of extravasation as the adverse event rate is not zero. 

Pancaro C et al 2019 [2]

What They Did:

• Multicenter, retrospective cohort study of a perioperative database from the University Hospitals in Amsterdam and Utrecht in the Netherlands
• Estimate the rate of occurrence of drug-related adverse effects (i.e. skin necrosis requiring surgical management) when dilute norepinephrine (20ug/mL) peripheral extravasation occurs in patients undergoing elective surgery under general anesthesia
• Standard peripheral norepinephrine infusions used in this study were constituted at a concentration of 0.002% in NS so that the final dilution is 20ug/mL (Initial infusion dose of 0.01 – 0.02ug/kg/min and titrated as per desired targeted BP)

Outcomes:

• Primary: Adverse drug event linked to peripheral norepinephrine administration (i.e. extravasation associated with tissue injury requiring medical or surgical intervention)

Inclusion:

• Query of EMR of patients receiving perioperative norepinephrine
• Age ≥18 years of age
• General anesthesia used

Exclusion:

• Patients not receiving peripheral norepinephrine

 Results:

• 14,385 patients received norepinephrine via a peripheral continuous infusion
• Drug extravasation observed in 5 patients
• 5/14,385 = 0.035% (95% CI 0.011% – 0.081%)
  • 1 – 8 events/10,000 patients
• Zero related complications requiring surgical or medical intervention (95% CI 0% – 0.021%)
  • 0 -2 events/10,000 patients
• Of the 5 extravasation events:
  • Dose range 0.02 – 0.05 ug/kg/min
  • Total median infusion time 20 min (range 20 – 25min)
  • Median norepinephrine dose administered 40 ug (range 35 – 50ug)
  • Total estimated norepinephrine that extravasated 33 – 80ug (volume range 1.67 – 4mL)

Strengths:

• Large observational trial of >14,000 patients
• Assesses and important question where there is a paucity of high-quality data 

Limitations:

• Retrospective chart review, which means the data reviewed is only as good as the information that was entered into the EMR. In other words, the study may not have captured all complications leading to underreporting (i.e. selection bias)
• Low extravasation event rate does not allow for defining risk factors
• IVs placed in elective surgical patients are inherently different than those placed in emergency crashing patients
• Time from extravasation to detection was short in this study, resulting in low volume of extravasate. This may not extrapolate to patients receive infusions for longer periods of time

Discussion:

• Critically ill patients are different than elective surgical cases:
  • Hypotentsion can affect tissue perfusion and the effect of extravasation in critically ill patients
  • Patients are monitored much more closely in the OR setting than what is possible in critically ill patients in the ED or ICU
  • IV placement is more difficult in critically ill patients, which means they have more potential to have extravasation
• The incidence of peripheral vasopressor extravasation in critically ill patients is higher than what is quoted in this study (i.e. 3 – 6%) of non-critically ill patients, but the incidence of tissue damage is also low.

Author Conclusion: “In the current database analysis, no significant association was found between the use of peripheral intravenous norepinephrine infusions and adverse events.” 

Clinical Take Home Point: In this study, the use of diluted norepinephrine administered by peripheral IV did not result in any complications requiring surgical or medical intervention. However these were small, diluted doses of norepinephrine and therefore not surprising we are not seeing skin necrosis. It is impossible to extrapolate the results of this study to critically ill patients.

Reversal of Extravasation Checklist (From EMCrit) [3]:

Although extravasation events are rare, if you are using peripheral pressors you should have a plan to treat extravasation events.

Initial Mangement

1. Switch Pressor to another IV, IO, or CVC
2. Leave cannula in and suck out as much as you can

SC & IV Phentolamine (Regitine)

1. Use 25g or smaller needle
2. Administer SC around the extravasation site (Place 5mg/1mL in 9mL of NS)
3. Through the catheter use 0.1 – 0.2 mg/kg (up to a max of 10mg)

Topical Nitroglycerin

1. 4mm/kg of 2% ointment to affected area
2. Can repeat dose in 8hrs

Terbutaline

1. Digital Extravasation: 0.5mg (1mg/mL) SC into area of extravasation
2. Extremity Extravasation: 1mg (1mg/10mL) SC into area of extravasation
3. Can repeat dose in 15min

Clinical Bottom Line:

In patients who are critically ill and requiring vasopressor treatment, the use of peripheral IVs are relatively safe with several caveats:

• Use an antecubital fossa or more proximal IV (These are generally larger veins which allow for larger IVs (i.e. 18g)
• Do not run the infusion for >2 – 4hrs
• Use as dilute a concentration as possible
• Use as small a volume as possible
• Have an IV observation protocol
• Have an extravasation protocol

References:

1. Tian DH et al. Safety of Peripheral Administration of Vasopressor Medications: A Systematic Review. EMA 2019. PMID: 31698544
2. Pancaro C et al. Risk of Major Complications After Perioperative Norepinephrine Infusion Through Peripheral Intravenous Lines in a Multicenter Study. Anesth Analg 2019. PMID: 31569163 
3. Plum M et al. Alternative Pharmacological Management of Vasopressor Extravasation in the Absence of Phentolamine. PT 2017. PMID: 28890646

For More Thoughts on This Topic Checkout:

• First10EM: An Update on Peripheral Vasopressors

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

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