Critical Care

The safety and efficacy of push dose vasopressors in critically ill adults

a b s t r a c t

Purpose: To evaluate practice patterns, efficacy, and safety of push dose pressors (PDP) in critically ill patients outside of the operating room (OR) at a large academic medical center.

Materials and methods: This was a single-center, retrospective cohort study (June 2018 to July 2020) conducted at a 1273-bed academic medical center. The primary outcome was efficacy, defined as a 25% increase in systolic blood pressure, and the cohort was analyzed according to PDP response (i.e. responders versus non- responders). A logistic regression model was used to assess predictors of response to PDPs. Safety outcomes included the incidence of hypertension, bradycardia, and tachycardia.

Results: 1727 patients were included in the final analysis. The median doses of phenylephrine and epinephrine administered were 400 ug (IQR 200-888 ug) and 50 ug (IQR 20-100 ug). The primary outcome was achieved in 102 (71.8%) patients in the epinephrine group and 1140 (55.9%) of patients in the phenylephrine group. Adverse effects after PDP receipt were minimal, with the most common being hypertension in 6.6% and 13.4% of the phenylephrine and epinephrine groups respectively.

Conclusions: This study demonstrates that PDP phenylephrine and epinephrine are safe and efficacious in treating the acute hypotensive period.

(C) 2022

  1. Introduction

acute hypotension in the intensive care unit (ICU) and emergency department (ED) is associated with increased morbidity and mortality [1-4]. Historically, this acute hypotension was managed with continu- ous vasopressor infusions. However, peripherally administered “push dose pressors” (PDPs) are being utilized more frequently for manage- ment of acute hypotension in a variety of clinical scenarios.

Phenylephrine and epinephrine are the two most common vaso- pressors administered as PDPs. Phenylephrine exerts its effects via ?-adrenergic activity resulting in vasoconstriction; epinephrine has both ? and ?-adrenergic activity, resulting in vasoconstriction and in- creased cardiac contractility [5-7]. Each drug has an onset of action of approximately one minute, making them attractive agents for bolus ad- ministration during emergent and transient hypotensive episodes. However, each agent has potential for adverse effects including Reflex bradycardia and a decrease in stroke volume associated with phenylephrine, and tachycardia and hypertension associated with epinephrine.

Abbreviations: PDP, push dose pressor; OR, operating room; ICU, intensive care unit; ED, emergency department; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; PRBCs, packed red blood cells.

* Corresponding author.

E-mail address: [email protected] (S. Singer).

Overall, there is a lack of data on PDP use outside of the operating room (OR), yet PDP use in the critically ill is increasing in frequency in the ED and ICU [4,7-10]. This has left a knowledge gap regarding prac- tice patterns, efficacy, and safety in critically ill patients.

The objectives of this study were to: 1) describe PDP practice pat-

terns in critically ill patients and 2) assess the efficacy and safety of PDP use for the treatment of acute hypotension. We hypothesized that PDPs would be used for a variety of clinical indications and have a favor- able benefit:risk profile in terms of efficacy and adverse events.

  1. Materials and methods

This was a single-center, retrospective cohort study (June 1, 2018 to July 31, 2020) of adults (age >= 18 years) receiving a PDP. This study was conducted at an urban academic tertiary care medical center with 1200 beds and a level 1 trauma center. The 70-bed ED services 80,000 to 90,000 patient visits per year and the institution has 173 relevant ICU beds. This study was approved by the Human Research Protection Office with waiver of informed consent, as well as the Protocol Review and Monitoring Committee.

Patients were identified using a pharmacy informatics database query. Patients were included if they received at least one bolus dose of phenylephrine pre-filled syringe or epinephrine pre-filled syringe. As a result of increasing PDP use at our institution, in August of 2015, we developed a PDP protocol that restricted use to emergent, urgent,

https://doi.org/10.1016/j.ajem.2022.08.055

0735-6757/(C) 2022

or anticipation of acute hypotension episodes. PDPs are stored sepa- rately in automated dispensing cabinets in the ED and all ICUs. Two pre-made PDP options are available for use: epinephrine (10 ug/mL, 10 mL syringe) and phenylephrine (100 ug/mL, 10 mL syringe). Syringes are purchased from a wholesaler, QuVa Pharma, Inc., or compounded in-house if unavailable. Syringes compounded in-house are stable at Room temperature for 24 h or refrigerated for 9 days per internal stabil- ity data (Supplementary Material 1). To improve patient safety, our in- stitution does not allow for preparation/dilution of PDPs at the bedside. All PDPs are labeled per the American Society for Testing and Materials International Standards endorsed by the American Society of Anesthesi- ologists to appropriately differentiate from other medications [11]. Phenylephrine bolus doses from 100 to 200 ug and epinephrine 10 to 20 ug administered every 2 to 5 min were recommended pursuant to a provider order. The ORs were not included in this practice change as they were operating with a different documentation system and the use of PDPs was well-established in this area. Patients that were preg- nant, received phenylephrine for epistaxis or priapism, had missing vital sign data (SBP, DBP, or heart rate) within 60 min prior to and after PDP administration, or received a PDP in the OR or an ancillary pro- cedure area were excluded. Patients that received both epinephrine and phenylephrine in a single episode were excluded from the analysis.

The primary outcome was efficacy, defined as a 25% increase in SBP post-PDP administration. Based on the primary outcome, the cohort was divided into responders (>=25% increase in SBP) or non-responders (<25% increase in SBP) [7]. Secondary outcomes were related to safety and included: 1) the incidence of hypertension, defined as blood pres- sure greater than 180/110 mmHg within 60 min of PDP administration;

2) bradycardia, defined as heart rate less than 60 beats per minute within 60 min of phenylephrine administration; and 3) tachycardia, defined as a 30% increase in heart rate from baseline within 60 min of epinephrine administration [12]. Additional outcomes included changes in SBP and DBP (i.e., lowest versus highest) 60 min pre- and post- administration, initiation of a continuous vasopressor infusion within 60 min after PDP administration, requirement of a dose increase of con- tinuous vasopressor support within 4 h of PDP administration, cardiac arrest within 60 min of PDP administration, ICU and hospital length of stay, in-hospital mortality, extravasation, and severe adverse events. Severe adverse events were defined as administration of atropine for bradycardia within 60 min of phenylephrine administration or hyper- tension requiring the administration of an antihypertensive agent within 60 min of PDP administration. To further describe safety, we que- ried our safety event reporting database for relevant events pertaining to PDP use. Finally, we assessed adherence to our institution’s criteria for PDP use via the following: use of epinephrine in patients with car- diac dysfunction and use of phenylephrine in patients without cardiac dysfunction. Cardiac dysfunction was defined as a left ventricular ejection fraction (LVEF) less than 40% [13].

Data were collected en masse via an informatics query. To ensure

accuracy, the first author validated 25% of retrieved data. If data were collected manually, only the first author participated in data collection. Demographic data, modified APACHE II score, Charlson Comorbidity Index, hospital and ICU length of stay, discharge disposition, hemody- namic data, laboratory values, and data related to PDP including time of initiation and dose were collected [14,15]. Additional data collected included interventions with potential to influence hemodynamics, including sedatives, blood products, paralytics, and intravenous fluid boluses.

All study definitions were chosen a priori. As patients often have multiple occurrences of PDP administration during an admission, we defined an “episode” as PDP administration during a 2-h period [7]. PDP administration outside of this time was classified as a separate event. SBP and DBP from 60 min prior and 60 min after PDP administra- tion were collected using the highest of multiple values and the lowest of multiple values respectively. If patients were initiated on a vasopres- sor infusion, the infusions were assumed to be indicated for an acute

hypotensive event, unless otherwise specified. Cardiac dysfunction was assessed via reported previous diagnoses of heart failure or echo- cardiogram collected within 72 h of PDP administration.

    1. Data analysis

Descriptive statistics were used to characterize the study sample and current PDP practice at our institution. Comparisons between groups were made using the Chi Squared test for categorical variables and the Mann-Whitney U or Wilcoxon Signed Rank Test for continuous variables as appropriate. A p-value <0.05 was regarded to be statistically signifi- cant. To further classify variables associated with response to PDPs, we utilized a multivariable logistic regression model, considering the clini- cal plausibility of covariates, p < 0.1 on univariable analysis, assessment of collinearity, and prior literature to determine the odds ratio (OR) and 95% confidence interval of the covariate’s effects on the primary out- come [4,7-9]. Statistical analyses were conducted using IBM SPSS Statis- tics 25 for Windows.

  1. Results

1727 patients (n = 2183 PDP episodes) were included in the final analysis (Fig. 1). Table 1 shows the baseline characteristics of the cohort. Overall, the mean increase in SBP, DBP, and MAP for the cohort after PDP administration was 45.3%, 54.9%, and 46.1% respectively.

    1. Phenylephrine

There were 1140 (55.9%) phenylephrine episodes that achieved a >= 25% increase in SBP and 901 (44.1%) that did not. Episodes that achieved a >= 25% increase in SBP were classified as responders. Phenyleph- rine responders were older, had a higher APACHE II score, and received inotropes less frequently (3% versus 5.5%, p = 0.004) than non- responders (Table 1). Responders received a higher median weight- based phenylephrine dose of 5.5 ug/kg versus 4.8 ug/kg (p = 0.037).

More responders experienced hypertension within 60 min post- administration (8.4% versus 4.2%, p < 0.001) (Table 2). A total of 9 patients received an IV antihypertensive, but there was no difference in IV antihypertensive use between groups (Table 2).

Phenylephrine responders had a significantly greater change in SBP, DBP, and MAP (Table 1). Responders were more frequently initiated on a continuous vasopressor and received more rate increases more often than non-responders (Table 2). Furthermore, more phenylephrine re- sponders had a rate increase of continuous vasopressor infusion than non-responders (22.4% versus 15.5%, p < 0.001). There was no differ- ence in hospital mortality between groups (Table 2). ICU and hospital length of stay were longer in responders (8 and 14.5 days respectively, p = 0.007) than non-responders (9 and 17 days respectively, p = 0.001). Responders more frequently received crystalloid boluses, PRBCs, and sedation (Table 3).

Among covariates assessed in our multivariable logistic regression model, receipt of crystalloid boluses (OR 0.639, 95% CI 0.432-0.946), PRBCs (OR 0.303, 95% CI 0.099-0.935), or a continuous vasopressor in- fusion within 60 min after PDP administration (OR 0.595, 95% CI 0.400-0.885) were associated with a lack of response to phenylephrine, while administration of any sedative was associated with response to phenylephrine (OR 1.75, 95% CI 1.136-2.695).

    1. Epinephrine

There were 102 (71.9%) epinephrine responders and 40 (28.2%) non-responders. Baseline characteristics were generally well balanced between groups except epinephrine responders were more commonly white and had higher APACHE II scores. Complete demographics are available in Table 1.

3175 patients evaluated for inclusion

1448 patients excluded:

  • PDP administration in the OR or ancillary procedure areas (N = 1348)
  • <18 years of age (N = 8)
  • Receipt of both agents (N = 75)
  • Pregnant (N = 17)

Fig. 1. Patient flow diagram.

Phenylephrine 1604 patients

2041 episodes

901

non- responders

1140

responders

Epinephrine 123 patients

142 episodes

40

non- responders

102

responders

Epinephrine responders had a greater increase in SBP, DBP, and MAP compared to non-responders (Table 1). More epinephrine responders were initiated on a continuous vasopressor infusion 60 min prior to PDP administration than non-responders (32.4% versus 15%, p = 0.037) (Table 2). There were no differences in hypertension or tachycar- dia between responders or non-responders (Table 2). No severe adverse events occurred in the epinephrine cohort; however, one event was re- ported in a query of our internal safety event database in which a pa- tient was reportedly administered a 1 mg dose of epinephrine in error due to a 100 ug/mL syringe being pulled from the automated dispensing cabinet rather than a 10 ug/mL syringe prior to pharmacist verification. There were no differences in cardiac arrest within 60 min of PDP admin- istration, in-hospital mortality, ICU or hospital length of stay between responders and non-responders (Table 2). Furthermore, there were no differences in administration of agents known to affect hemodynamics between groups (Table 3).

Regarding the multivariable logistic regression model, history of congestive heart failure was associated with response to epinephrine (OR 11.889, 95% CI 1.030-137.257). Covariates included APACHE II score, weight-based dose, cardiac dysfunction, and continuous vaso- pressor use within 60 min prior to PDP administration (Table 4).

  1. Discussion

Despite PDP use being common practice at our institution and others, available data are lacking to support their use. Our study in- cluded the largest cohort of patients in the ED to date in addition to pa- tients admitted to a variety of ICUs. Prior literature primarily focused on safety and Medication errors, and while we did the same, we also assessed variables associated with PDP response.

Overall, 56% of patients that received phenylephrine and 70% of pa- tients that received epinephrine achieved a 25% increase in SBP. As ex- pected, both agents improved SBP, DBP, and MAP. Notably,15.5% and 27.5% in the phenylephrine and epinephrine groups respectively re- ceived continuous vasopressor infusions within the 60 min before PDP administration, and 46.3% and 74.6% received vasopressor infusions within the 60 min after PDP administration. We suspect that these re- sults are due to PDP use as a bridge to continuous vasopressor infusion

at our institution and are consistent with previous studies that describe a similar practice pattern [8,9].

It is also pertinent to note that administration of crystalloid boluses and PRBCs were associated with a lack of response to phenylephrine, possibly indicating that hypotension may have been adequately man- aged with preload expansion. A similar observation was seen in a study by Schwartz and colleagues. In their study, patients that received

>30 mL/kg of fluids prior to phenylephrine administration received fewer and lower cumulative phenylephrine doses. These findings, along with those from our study, highlight the importance of adequate preload expansion in the treatment of acute hypotension. While we found an association between fluid boluses and lack of phenylephrine response, we could not evaluate patient fluid status due to documenta- tion limitations in the electronic health record.

Conversely, administration of any sedative was predictive of phenyl- ephrine response. PDPs are often administered to counteract hypoten- sion during the peri-intubation period in which sedatives are used for induction [4,7-9]. The mechanism of peri-intubation hypotension is multifactorial including vasoplegia from administration of induction medications, loss of intrinsic adrenergic tone, worsening acidosis due to apnea, and reduced venous return after initiation of positive pressure ventilation [16-19]. While we cannot confirm that all sedatives in this study were administered for induction during rapid sequence intuba- tion (RSI), we suspect that PDPs were administered in this context as is common practice at our institution. Furthermore, this finding would be consistent with PDP use seen in previous literature in which peri- intubation hypotension was the most common indication for PDP use [4,7,8].

Adverse events were uncommon, and no patients experienced se- vere adverse events in our study. The most common adverse event was hypertension, occurring in 134 (6.5%) patients in the phenyleph- rine group and 17 (12%) patients in the epinephrine group. Only 4 pa- tients, however, received an IV antihypertensive. Due to lack of available documentation and the retrospective design of our study, we were unable to ascertain occurrence of ventricular dysrhythmias related to PDP administration in our study. While we cannot draw conclusions on clinical outcomes or mortality, these data suggest that PDPs may be safely administered to treat acute hypotension, however, further

Table 1

Patient Characteristics and Efficacy Outcomes

Phenylephrine

Epinephrine

Responders

Non-responders

p value

Responders

Non-responders

p value

(n = 1140)

(n = 901)

(n = 102)

(n = 40)

Gender, male

640 (56.1)

516 (57.3)

0.609

54 (52.9)

28 (70)

0.064

Race

White

747 (65.5)

600 (66.6)

0.614

57 (55.9)

15 (37.5)

0.049

Black

343 (30.1)

265 (29.4)

0.740

39 (38.2)

20 (50)

0.201

Asian

18 (1.6)

9 (1)

0.255

1 (1)

1 (2.5)

0.489

Native American

0

3 (0.3)

0.051

0

0

NS

Pacific Islander

3 (0.3)

3 (0.3)

0.772

0

0

NS

Other1

5 (0.4)

7 (0.8)

0.321

0

0

NS

Unknown

24 (2.1)

14 (1.6)

0.360

5 (4.9)

4 (10)

0.262

Age (years)

64 (53-71)

61 (49-72)

0.029

65.5 (49-75)

67 (51.5-76.3)

0.808

Weight (kg)

81 (65-100)

82 (67-99)

0.667

80 (63-95)

81 (75-99)

0.215

Charlson Comorbidity Index2

4 (2-6)

3 (2-6)

0.736

3 (2-5)

3 (1-7)

0.394

APACHE II Score1

18 (15-22)

17 (14-20)

<0.001

21 (18-24)

18 (15-22)

0.007

History of CHF3

40 (12.7)

24 (11.9)

0.809

9 (26.5)

5 (35.7)

0.522

CRRT

54 (4.7)

47 (5.5)

0.453

13 (12.7)

2 (5)

0.177

Continuous vasopressor 60 min prior to PDP administration

213 (18.7)

103 (11.4)

<0.001

33 (32.4)

6 (15)

0.037

Administration of inotropes4

34 (3)

50 (5.5)

0.004

8 (7.8)

4 (10)

0.678

Episode Location

ED

173 (15.2)

61 (6.8)

<0.001

51 (50.0)

17 (42.5)

0.421

ICU

912 (80.0)

818 (90.8)

<0.001

50 (49.0)

22 (55.0)

0.521

Floor

55 (4.8)

22 (2.4)

0.005

1 (1)

1 (2.5)

0.489

Cardiac dysfunction5

32 (10.1)

20 (10.0)

0.948

10 (29.4)

4 (28.6)

0.954

Indication

Dose per episode, ug

500 (200-900)

400 (200-800)

0.048

60 (30-100)

50 (20-100)

0.291

Dose per episode, ug/kg

5.5 (2.8-10.4)

4.8 (2.5-9.6)

0.037

0.7 (0.3-1.6)

0.6 (0.3-1)

0.275

Primary Outcome

Baseline SBP, mm Hg

75 (65-87)

104 (89-123)

<0.001

72 (58-89)

108 (87-135)

<0.001

Baseline DBP, mm Hg

46 (37-53)

61 (51-73)

<0.001

43 (33-54)

59 (51-68)

<0.001

Baseline MAP, mm Hg

56 (48-64)

76 (65-89)

<0.001

52 (43-66)

75 (63-90)

<0.001

Change in SBP, mm Hg

45 (32-66)

7 (-4-15)

<0.001

60 (39-84)

3 (-4.8-14)

<0.001

Change in SBP, %

58.6 (38.3-93)

7 (-3.4-15.4)

<0.001

83.8

3.4 (-3.9-12.2)

<0.001

Change in DBP, mm Hg

28 (17-41)

5 (-2-13)

<0.001

(54.6-132.4)

38 (24-50)

6.5 (-2-22)

<0.001

Change in DBP, %

61.3 (36.5-100)

7.8 (-3.9-22.2)

89.3

10.9 (-3.5-33.4)

<0.001

Change in MAP, mm Hg

33 (23-47)

5 (-3-12)

<0.001

(47.1-135.6)

45 (30.5-60)

2.5 (-1.8-16.8)

<0.001

Change in MAP, %

6.6

57.1 (37.8-90)

<0.001

84.3

3.4 (-1.6-21.5)

<0.001

(-3.2-17.4)

(52.4-131.2)

All data presented as n (%) or median (IQR) as appropriate.

CHF = congestive heart failure, CRRT = Continuous renal replacement therapy, DBP = diastolic blood pressure, MAP = mean arterial pressure, SBP = systolic blood pressure.

1 Other = Alaska Native or denoted in chart as “other”.

2 Upon hospital admission.

3 In patients that had an echocardiogram performed within 72 h of PDP administration.

4 Dobutamine or milrinone.

5 As defined by left ventricular ejection fraction <40% on echocardiogram within 72 h of PDP administration.

evaluation of cardiac dysrhythmias is necessary. Furthermore, these re- sults are consistent with previous literature evaluating PDP use [4,7-9]. Additionally, only one event was reported to our internal safety event database in which the wrong concentration of epinephrine was pulled from the automated dispensing cabinet (100 ug/mL instead of 10 ug/mL) resulting in administration of a 1 mg dose of epinephrine in error. Upon review of this event, the patient did not experience any ad- verse effects due to the administration error. Reporting of events, how- ever, is voluntary, so it is possible that some events may not be accounted for. Notably, our institution does not allow for dilution of PDPs at the bedside, therefore removing a source of error that may be present at other institutions and likely contributing to the low number of adverse events identified in our study. Previous studies have demon- strated that PDPs, particularly epinephrine, are prone to human error due to bedside dilution or the availability of different drug concentra- tions [10,20,21]. In a study by Cole and colleagues, human errors were observed in 19% of patients who received PDPs and of these errors, 3% resulted in administered doses 2.5 to 100-fold higher than intended [20]. Of patients that received epinephrine in their study, hemodynamic events occurred less frequently when patients received doses that were

diluted at the bedside. In a recent study by Nam and colleagues in which premixed phenylephrine and epinephrine syringes were readily avail- able, dosing errors occurred in 12.8% and 2.1% of patients who received epinephrine and phenylephrine respectively. The authors hypothesize that the increased incidence of epinephrine dosing errors was likely due to the availability of multiple epinephrine concentrations for differ- ent indications (i.e., cardiac arrest, anaphylaxis). Given the aforemen- tioned dosing error reported at our institution, we agree with their hypothesis and as such, store various epinephrine products separately in the automated dispensing cabinet. These data, along with the low ad- verse event rate reported in our study, demonstrate the importance of availability of pre-made PDP syringes and proper labeling, storage, and staff education for PDPs.

Due to its inotropic and chronotropic effects, epinephrine is often fa- vored over phenylephrine in patients with cardiac dysfunction to in- crease cardiac output. Furthermore, reflex bradycardia associated with phenylephrine can pose further detriment to patients with underlying cardiac dysfunction. At our institution, use criteria reflect this practice and delineate that patients with cardiac dysfunction should preferen- tially receive epinephrine over phenylephrine. In our study, we assessed

Table 2

Safety Outcomes

Phenylephrine

Epinephrine

Responders

Non-Responders

p value

Responders

Non-responders

p value

(n = 1140)

(n = 901)

(n = 102)

(n = 40)

Hypertension

96 (8.4)

38 (4.2)

<0.001

17 (16.7)

2 (5)

0.066

Hypertension requiring IV antihypertensive

4 (0.4)

5 (0.6)

0.490

0

0

NS

Bradycardia (phenylephrine)

23 (2.0)

13 (1.4)

0.327

Tachycardia (epinephrine)

46 (45.1)

13 (32.5)

0.171

Extravasation requiring phentolamine or terbutaline

0

0

0

0

NS

Cardiac arrest (60 min post PDP)

72 (6.3)

37 (4.1)

0.0028

22 (21.6)

9 (22.5)

0.904

Continuous vasopressor 60 min after PDP administration

605 (53.1)

340 (37.7)

<0.001

77 (75.5)

29 (72.5)

0.713

Rate increase of continuous vasopressor within 4 h of PDP

255 (22.4)

140 (15.5)

<0.001

48 (47.1)

17 (42.5)

0.624

administration

Time to continuous vasopressor initiation, minutes1

9 (2-24)

10 (2-29)

0.313

8 (2-27)

10 (4-32)

0.310

Vasopressor

Dopamine

1 (0.1)

0

0.374

0

0

NS

Epinephrine

11 (1.0)

11 (1.2)

0.578

2 (2)

6 (15)

0.002

Norepinephrine

150 (13.2)

88 (9.8)

0.018

13 (12.7)

6 (15)

0.723

Phenylephrine

33 (2.9)

20 (2.2)

0.341

1 (1)

0

0.530

Vasopressin

20 (1.8)

6 (0.7)

0.029

3 (2.9)

1 (2.5)

0.886

More than one

44 (3.9)

34 (3.8)

0.920

15 (14.7)

3 (7.5)

0.246

No vasopressors

881 (77.3)

742 (82.4)

0.005

68 (66.7)

24 (60)

0.454

ICU length of stay (days)

8 (3-17)

9 (4-18)

0.007

3 (1-11)

4 (1-9)

0.746

Hospital length of stay (days)

14.5 (7-28)

17 (8-30.5)

0.001

8 (1-18)

8 (1-23)

0.926

In-hospital mortality

322 (28.2)

239 (26.5)

0.388

39 (38.2)

13 (32.5)

0.523

All data presented as n (%) or median (IQR) as appropriate.

Hypertension = blood pressure > 180/110 mmHg, tachycardia = heart rate increase >30%, bradycardia = heart rate < 60 bpm.

1 Time to continuous vasopressor initiation when started within 60 min of PDP administration.

response to PDPs in patients with and without cardiac dysfunction (de- fined as LVEF <40% on echocardiogram within 72 h of phenylephrine receipt or history of heart failure) [13]. There were no differences in re- sponse to either agent in patients with cardiac dysfunction or history of heart failure. We also assessed cardiac dysfunction and history of con- gestive heart failure as covariates in our multivariable logistic regression analysis. Interestingly, history of CHF was associated with epinephrine

response (OR 11.889, 95% CI 1.030-137.257). Due to the small sample size of our epinephrine cohort, further studies are warranted to deter- mine the effects of cardiac dysfunction on PDP response.

Strengths of this study include that it is the largest study assessing PDP use to date, PDP use was assessed in a variety of settings outside of the OR including multiple ICUs and the ED, data describing agents known to affect hemodynamics were collected, and the presence of

Table 3

Hemodynamic Influencers within 60 Minutes of PDP Administration Variables Expected to Increase MAP

Phenylephrine

Epinephrine

Responders (n = 1140)

Non-Responders (n = 901)

p value

Responders (n = 102)

Non-Responders (n = 40)

p value

Crystalloid bolus

484 (42.5)

263 (29.2)

<0.001

46 (45.1)

13 (32.5)

0.171

Blood Products

Albumin

64 (5.6)

43 (4.8)

0.397

5 (4.9)

1 (2.5)

0.522

FFP

18 (1.6)

12 (1.3)

0.645

1 (1)

1 (2.5)

0.489

pRBCs

92 (8.1)

21 (2.3)

<0.001

16 (15.7)

4 (10)

0.381

Ketamine

176 (15.4)

118 (13.1)

0.135

27 (26.5)

5 (12.5)

0.073

Variables Expected to Decrease MAP

Any Antihypertensive

4 (0.4)

5 (0.6)

0.490

0

0

NS

Hydralazine

0

0

NS

0

0

NS

Labetalol

0

3 (0.3)

0.051

0

0

NS

Enalaprilat

0

0

NS

0

0

NS

Nicardipine

0

1

0.261

0

0

NS

Clevidipine

0

1

0.261

0

0

NS

Esmolol

4 (0.4)

0

0.075

0

0

NS

Any sedative

704 (61.8)

436 (38.2)

0.001

60 (58.8)

23 (57.5)

0.886

Etomidate

228 (20)

154 (17.1)

0.094

15 (14.7)

11 (27.5)

0.076

Fentanyl

443 (38.9)

349 (38.7)

0.954

31 (30.4)

15 (37.5)

0.416

Propofol

181 (15.9)

250 (27.7)

<0.001

9 (8.8)

5 (12.5)

0.509

Midazolam

361 (31.7)

323 (35.8)

0.047

23 (22.5)

15 (37.5)

0.070

Any paralytic

379 (33.2)

287 (31.9)

0.505

36 (35.3)

12 (30)

0.549

Rocuronium

296 (26)

230 (25.5)

0.822

18 (17.6)

3 (7.5)

0.125

Succinylcholine

88 (7.7)

64 (7.1)

0.599

18 (17.6)

9 (22.5)

0.507

Vecuronium

2 (0.2)

0

0.208

0

0

NS

All data presented as n (%) or median (IQR) as appropriate.

All agents administered within 60 min pre or post PDP administration. FFP = fresh frozen plasma, pRBCs = Packed red blood cells.

Table 4

Predictors of PDP Response

Variable

Odds Ratio

95% CI

Predictors of Phenylephrine Response

Age

1.001

0.989-1.013

Inotrope

1.486

0.615-3.591

APACHE

1.016

0.978-1.055

Weight-based dose

1.004

0.988-1.021

Cardiac dysfunction

1.075

0.580-1992

Crystalloid bolus

0.633

0.428-0.937

Packed red blood cells

0.328

0.099-0.935

Any sedative

1.750

1.136-2.695

Continuous vasopressor 60 min prior to PDP

0.663

0.375-1.174

Declaration of Competing Interest

None.

Acknowledgements

The authors would like to acknowledge Nicholas Hampton, PharmD, for his assistance with data acquisition and Kevin Betthauser, PharmD, BCCCP, for his assistance with data analysis.

administration

Continuous vasopressor 60 min after PDP administration

Predictors of Epinephrine Response

0.597 0.402-0.887

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2022.08.055.

APACHE 1.097 0.920-1.307

Weight-based dose 2.675 0.616-11.621

Cardiac dysfunction 0.520 0.076-3.573

CHF 11.889 1.030-137.257

References

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Continuous vasopressor 60 min prior to PDP administration

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cardiac dysfunction was assessed. We believe these data provide further

support that PDP phenylephrine and epinephrine are safe and effica- cious in increasing blood pressure in the acute hypotensive period.

Despite attempting to address gaps in present literature, our study has several limitations. Due to its retrospective design, we were unable to control for many potential confounding factors and were reliant on information documented in the electronic health record. We were also unable to collect data on individual bolus doses because this documen- tation was not consistently available. Documentation was also often in- complete or unclear due to the high-stress nature of the timeframe surrounding administration of these agents. Finally, we were unable to assess patient-centered clinical outcomes such as mortality or ICU length of stay.

  1. Conclusions

The results of this study add to the available body of literature dem- onstrating that PDPs are efficacious in increasing blood pressure during the acute hypotensive period in the ED and ICU. Further studies assessing which patient populations may benefit from PDPs, assessment of comparative efficacy and safety of different agents, and further anal- ysis of long-term clinical outcomes are warranted and would provide further insight into appropriate PDP use.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Sarah Singer: Writing – review & editing, Writing – original draft, Visualization, Validation, Project administration, Methodology, Investi- gation, Formal analysis, Data curation, Conceptualization. Hannah Pope: Writing – review & editing, Supervision, Methodology, Formal analysis. Brian M. Fuller: Writing – review & editing, Methodology, Conceptualization. Gabrielle Gibson: Writing – review & editing, Super- vision, Methodology, Formal analysis, Conceptualization.

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