Critical Care, Critical Care Alert, Shock

Critical Care Alert: 2 Studies Shed Light on Efficacy, Effects of Peripheral IVs for Vasopressors

Critical Care Alert

The administration of vasopressor support is common practice in emergency departments in the setting of critically ill patients. Timely administration of pressors has been known to save lives. In fact, a delay in a single hour increased overall in-hospital mortality risk by 2%. 

Thus, quickly assessing the need for pressor support is of paramount importance regardless of the etiology of shock. In practice, there remains a longstanding concern surrounding giving vasopressors through peripheral IVs. The concerns include, but not limited to discomfort at the injection site and the risk of extravasation with subsequent necrosis. Central venous access, on the other hand, utilizes larger vessels and decrease the risk of extravasation and limb ischemia that can result from it. Although the widespread use of ultrasound guidance has further decreased the risks that were once associated with placing a central line - pneumothorax and arterial puncture, it can still result in a significant delay in starting pressors. Items such as gathering supply, acquiring consent, placement of the central line, and post-placement chest x-ray prior to use can add delay to patient care. Thus, we discuss two different meta-analyses below that examine the prevalence of complications that could result from peripheral infusion of vasopressors.

Additionally, mean arterial pressure (MAP) goals have been evaluated to determine the ideal range to support end-organ perfusion. Standard of care at this time recommends MAP goals of 60 to 70 mm Hg and a recent meta-analysis examining 6 RCTs with more than 3500 patients concluded higher MAP goals did not have a significant impact on mortality, duration of mechanical ventilation, or ICU length of stay. Our second article examines the effect of transient hypotension, focusing on mean perfusion pressure (MPP), which is the difference between MAP and central venous pressure (CVP). 

These articles blend together the important concepts of the impact of transient hypotension and what should be done about it in the emergency department in regard to vasopressor support. If peripheral vasopressors are deemed to be safe to use, should we be tolerating hypotension with low MAPs just because central venous access has not been obtained? Or should we be aggressive with early vasopressor support, regardless of central access, to maintain MAP goals and prevent end-organ hypoperfusion?

Study #1: Tran QK, Mester G, Bzhilyanskaya V, et al. Complication of Vasopressor Infusion Through Peripheral Venous Catheter: A Systematic Review and Meta-Analysis. Am J Emerg Med. 2020;38(11):2434-2443.

Objective
To assess literature involving the prevalence of complications from infusing vasopressors via peripheral intravenous catheters

Design
Random-effects meta-analysis

Trial Selection
325 studies investigating complications as direct results from the infusion of vasopressors through peripheral intravenous catheters were identified. These included prospective randomized control trials, quasi-randomized control trials, observational prospective, and retrospective trials. Case reports, non-English studies, and non-full-text studies were excluded

Of 325 studies originally identified, 299 were excluded after initial screening and only 9 full-text articles met eligibility requirements for quantitative analysis. Only one randomized control trial.

The meta-analysis included 1835 patients.

Primary Outcome
Any complication as a direct result of peripheral infusion of vasopressors

Secondary Outcomes
Any treatment for complications (amputation, debridement, cold compression, hot compression, pain medication, observation, local infiltration of phentolamine)

Key Results
9 studies were included in the review: 8 observational and 1 randomized control study

Primary Outcomes
From the one randomized control trial:

  • 122 total adverse events - 96% were minor and 4% major

Pooled meta-analysis showed low prevalence of complications. The most common complications were:

  • 72% infiltration
  • 21% erythema
  • 4% peripheral thrombosis

Secondary Outcomes (adverse events)
No significant results reported

Strengths

  • Meta-analysis
  • Large patient population (1835)

Limitations

  • Lack of mention of patient demographics or clinical indicators that would increase/decrease the risk of complication
  • Only 1 randomized control trial
  • Bias between studies regarding objective measures of complications (such as, "what constitutes an infiltration")
  • Lack of consistency in reporting of pressor dose between trials

EM Takeaway

  1. Very low complication risk when pressors were given through a peripheral line
  2. A 2% increase in mortality for every hour of delay in pressors initiation in critically ill patients 
  3. Thus, initial administration of these medications should be started through peripheral IVs as soon as possible 

Study 2: Panwar R, Tarvade S, Lanyon N, et al. Relative Hypotension and Adverse Kidney-related Outcomes among Critically Ill Patients with Shock. A Multicenter, Prospective Cohort Study. Am J Respir Crit Care Med. 2020 Nov 15;202(10):1407-1418. 

Objective
To investigate the magnitude of relative hypotension during vasopressor support among critically ill patients with shock and to determine whether such relative hypotension is associated with new significant acute kidney injury (AKI) or major adverse kidney events (MAKE) within 14 days of vasopressor. 

Design
An investigator-initiated, multicenter, prospective observational cohort study in mixed medical-surgical ICUs at 7 university-affiliated tertiary-care hospitals in Australia

Population
Inclusion Criteria:

  • >40 years old
  • Within 48 hours of ICU admission
  • Receiving vasopressor support and/or inotropic medication for at least 4 hours for a suspected shock state
  • Receiving respiratory support with high flow nasal cannula or positive-pressure ventilation

Exclusion Criteria:

  • Moribund state
  • Renal failure w/ imminent need for renal replacement therapy
  • End-stage renal disease
  • Lack of central venous catheter
  • Trauma as main reason for current admission to ICU
  • Active bleeding
  • Unavailability of at least two pre-illness blood pressure readings
  • Prior enrollment in this study
  • Pregnancy
  • Need for extracorporeal support
  • Any condition specifically requiring a higher or lower blood pressure target in view of a treating clinician

Study Variables

  • The key blood pressure parameter for the study was Mean Perfusion Pressure (MPP).
  • Basal MPP, mean arterial pressure (MAP), and central venous pressure (CVP) were estimated.
  • 5 different pre-illness MAP values or blood pressure readings at least 12 hours apart over 3 years prior were taken and averaged
  • Measured every 4 hours for 120 hours
  • MPP
  • Achieved MAP
  • Norepinephrine equivalent dose

Exposure Variables

  • Relative hypotension quantified as time-weighted average MPP deficit for each patient
  • MPP deficit was defined as the percentage difference between patient’s pre-illness basal MPP and achieved MPP on vasopressor support
  • Negative MPP (or MPP surplus) considered a deficit of zero
  • Time-weighted average derived as aggregate area under the curve divided by cumulative exposure for each individual patient
  • Percentage of time points sent with MPP deficit > 20%
  • Time-weighted average MAP deficit and percentage of time points spent with MAP <65 mm Hg also measured

Outcomes
Primary:

  • Development of new significant AKI and MAKE within 14 days after T0
  • AKI defined as an increase of at least two AKI stages (i.e., peak serum creatinine level>2 times the baseline creatinine level at T0), as per the Kidney Disease: Improving Global Outcomes criteria for AKI
  • MAKE defined as a composite measure of death, new initiation of RRT, or doubling of serum creatinine from the premorbid level at Day 14
  • Secondary:
  • Degree of new AKI progression (i.e., maximum AKI stage reached) within 14 days
  • Peak percentage increase in serum creatinine from baseline at T0 among those who did not receive RRT
  • Receipt of RRT within 14 days, 
  • RRT-free days within 28 days
  • Incidence of de novo chronic kidney disease at 3 months,
  • MAKE-90, and Day 90 all-cause mortality
  • Death within 14 days

Key Results

  • 1 in 2 patients (52%) developed new AKI
  • Nearly 1 in 4 (24%) developed new significant AKI (>2 AKI stage increase) within 14 days from T0
  • Incidence of MAKE-14 was 29%
  • Greater percentage of patients in higher tertiles of MPP deficit and higher tertiles of percent of time spent with MPP deficit >20% developed new significant AKI and MAKE-14
  • Multivariate regression analysis
  • Every percentage increase in time-weighted average MPP deficit increased odds of developing new significant AKI by 5.6% (95% CI, 2.2-9.1, p=0.001)
  • Every percentage increase in time-weighted average MPP deficit increased odds of developing MAKE-14 by 5.9% (95% CI, 2.2-9.8, p=0.002)
  • Every percentage increase in percentage of time points with an MPP deficit >20% increased odds of developing new significant AKI by 1.2% (95% CI, 0.3-2.2, p=0.008)
  • Every percentage increase in percentage of time points with an MPP deficit >20% increased odds of developing MAKE-14 by 1.4% (95% CI, 0.3-2.4, p=0.004)
  • Relationships between the risks of developing new significant AKI or MAKE-14 and the time-weighted average as well as percentage of time spent with MAP <65 mm Hg were not statistically significant

Strengths

  • First prospective study to highlight the degree of relative hypotension inadvertently accepted in critically ill patients with non-hemorrhagic shock
  • Multi-center design
  • Multivariable adjusted relationships were examined over variable shorter and shorter time frames
  • Inclusion criteria allowed for focus on sicker patient population 
  • All patients eligible at T0 were retained for full follow up
  • Exclusion of patients requiring RRT at T0 

Limitations

  • Prospective, Observational, Cohort study
  • KDIGO criteria for AKI may have missed a portion of AKI’s
  • Potential for lead time bias, mitigated by multivariable analysis over multiple time frames
  • AKI after day 14 would not be accounted for
  • Not powered to detect differences in subgroups of shock (Septic vs cardiogenic) and associated AKI
  • Not powered to detect differences between MPP and MAP deficits and the associated effect on AKI

EM Take-Aways
This study is the first to examine the effect of relative hypotension on new acute kidney injury based on pre-illness blood pressure measurements. 

The importance of this study is two-fold: 

  1. Individualized blood pressure goals may be a consideration in the future when caring for the critically ill as pre-illness blood pressure is becoming easier to access and record with EMRs and may give some idea as to how much hypotension patients may tolerate and if they may require a different goal
  2. Relative hypotension and the length of time spent with that hypotension in individuals is associated with an increased incidence of new acute kidney injury.

In the emergency department, this matters because we care for the critically ill in their initial presentation, often initiating vasopressor support, invasive blood pressure monitoring modalities, and set the trajectory for the first few hours of care. This study demonstrated that relative hypotension for even brief amounts of time increased the incidence of acute kidney injury, which suggests that in the ED we should be considering individual blood pressure goals for our patients and be more vigilant about the degree of hypotension we tolerate and for how long. 

Furthermore, this study demonstrated that patients had relative hypotension when examining MPP. The same effect was not demonstrated with MAP levels < 65 mm Hg which is a standard goal in the care of the critically ill, suggesting that MAP goals may not be sufficient. 

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