Article, Emergency Medicine

The impact of push-dose phenylephrine use on subsequent preload expansion in the ED setting

a b s t r a c t

Background: The utilization of bolus-dose phenylephrine (PHE) has transitioned to the emergency department (ED) for the treatment of acutely hypotensive patients, despite a paucity of literature in this setting.

Methods: This was a single center retrospective chart review of the utilization of bolus-dosed PHE for acute hypo- tension in the ED at an academic non-forprofit hospital. The primary objective of this study is to report the fre- quency of patients that were initiated on a continuous vasopressor infusion (CVI) within 30 minutes after the first administration of bolus-dose PHE. Secondary objectives included an observational description of the impact of early preload expansion (fluids) on the initiation of CVIs in the setting of bolus-dose PHE in the ED.

Results: Seventy-three patients met inclusion criteria for analysis. The primary outcome, 46.5% (n = 34) of patients were initiated on a CVI within 30 minutes following bolus-dose PHE. Initial preload expansion (30 mL/kg of IV fluids) was found to be significantly disproportionate with 34.2% appropriately fluid challenged vs 65.8% (P = .0048). In addition, a significant decrease in the number of PHE bolus doses were required [1.5 vs

2.3 (P = .01)] in the adequately IVF challenged group.

For secondary endpoints, PHE was most commonly indicated for peri-intubation hypotension (n = 52, 71.2%). Significant adverse events were documented for 15 (20.5%) patients, with bradycardia (n = 7; 9.6%) as the most common adverse event.

Conclusions: Initial preload IVF expansion was found to be significantly disproportionate, and appears to be asso- ciated with an increase number of phenylephrine bolus doses in our study population.

(C) 2016

  1. Introduction

In the emergency department (ED), acute persistent hypotension is a potential indicator for impending circulatory failure that, if left un- treated, can lead to organ failure [1]. While hypotension occurs in roughly 1% of ED patients, in the septic patient population, it has been shown that non-sustained hypotension in the ED is an independent pre- dictor of in-hospital mortality (RR 2.8; 95% CI 1.5-5.2) [2,3]. In the ED, pathological hypotension can occur as a consequence of a variety of po- tential etiologies, including procedures and medication-related effects, in addition to the range of shock states that can present on evaluation. Treatment of acute hypotension aims to reverse the initial cause im- proving tissue perfusion. As etiology is typically unknown or may be

? The authors of this paper have no conflict of interest.

* Corresponding author. Tel.: +1 904 2444157 (Office); fax: +1 904 2444272.

E-mail addresses: [email protected] (M.B. Schwartz), [email protected] (J.A. Ferreira), [email protected] (P.M. Aaronson).

1 Tel.: +1904 244 9590 (Office); fax: +1904 244 9591.

2 Tel.: +1904 244 2213 (Office); fax: +1904 244 4272.

mixed, a general strategy may include maximizing intravascular volume and preload status followed by consideration of catecholamine therapy [4,5]. Phenylephrine (PHE) is a selective alpha-one adrenergic agonist commonly utilized in the procedural area, as a diluted peripheral intra- venous (IV) bolus for Rapid treatment as a treatment of non-sustained, anesthesia or medication-induced, hypotension [6-12]. The utilization of bolus-dose PHE has transitioned to the ED for the treatment of acutely hypotensive patients, despite a paucity of literature in this setting [13]. Little known literature exists outside of anesthesia-induced hypoten- sion. Overall, the indication of bolus-dose PHE in the acute care setting re- mains unclear, and the impact of other resuscitative therapies given in conjunction with PHE are not well described and may be circumvented. This study aims to describe the utilization of bolus-dosed PHE in the con- text of preload expansion and continuous vasopressor infusion (CVI)

therapy for the treatment of hypotension in the ED.

  1. Methods

This was a single center retrospective chart review of the utilization of bolus-dosed PHE for acute hypotension in the ED at an academic non-

http://dx.doi.org/10.1016/j.ajem.2016.09.041

0735-6757/(C) 2016

2420 M.B. Schwartz et al. / American Journal of Emergency Medicine 34 (2016) 24192422

for-profit hospital. Data was collected from electronic medical records Table 1

of patients receiving at least one order for a PHE prefilled syringe (100 Demographics and patient characteristics (n = 73)

ug/mL – 10 mL IV syringe) while in the ED from January 1, 2014 through n (%)

June 30, 2015. Patients were included if they were at least 18 years of

age with a documented administration of at least one IV bolus-dose of

Age (years) – median (IQR) Male

65 (57-75)a

44 (60.3%)

PHE. Patients were excluded if there was missing hemodynamic data

Female

29 (39.7%)

[Blood pressure , Heart Rate (HR)] before or within 1 hour after PHE was administered, if they were pregnant, or if PHE was used for treatment of priapism or epistaxis.

The primary objective of this study is to report the frequency of pa-

Primary diagnosis Septic Shock Respiratory Failure Miscellaneousb

Stroke (ischemic)

33 (45.2%)

14 (19.2%)

12 (16.5%)

5 (6.8%)

tients that were initiated on a CVI within 30 minutes after the first ad-

ministration of bolus-dose PHE. Secondary objectives included an

Cardiac Arrest Pulmonary Embolism

5 (6.8%)

4 (5.5%)

observational description of the impact of early preload expansion (fluids) on the initiation of CVIs in the setting of bolus-dose PHE in the ED. Indications, changes in patient hemodynamics (BP, HR) 1 hour following PHE, and the incidence of significant adverse effects were also observed.

In this study, indications for bolus-dose PHE were classified as peri- intubation hypotension, bridge to vasopressor infusion, and acute hypo- tension. These indications were extracted through chart review meeting specific definitions. Bolus-dose PHE for peri-intubation hypotension was defined as utilization of PHE within 60 minutes before or after intu- bation. Sixty minutes was used as a conservative parameter to decrease the likelihood of PHE indications classified as an alternative group in re- lation to the process of intubation. A bridge to vasopressor infusion (due to sustained hypotension) was defined as CVI therapy within 30 mi- nutes of the last PHE dose. Unless there was documentation of a specific event that may have induced or prolonged hypotension within 60 mi- nutes before or after the last PHE dose; CVI therapy was assumed to be for an acute hypotensive event. For the purpose of this study, patients were considered to have adequate therapeutic preload expansion if they received at least 30 mL/kg (actual weight) of crystalloid intrave- nous fluids in the ED prior to the time PHE was administered. Patient hemodynamic parameters [(HR, systolic and Diastolic BP, mean arterial pressure (MAP)] were recorded prior to the first dose of PHE and at least 60 minutes following PHE. Safety of PHE was described based on docu- mentation of significant adverse effects associated with PHE use; in- cluding reactive hypertension, hemorrhagic stroke/Intracranial bleeding, ventricular tachycardia, bradycardia or extravasation. Reactive hypertension was defined as documented systolic blood pressure (SBP) increased to greater than 180 mmHg within one hour after a PHE bolus. Intracranial hemorrhage was defined as any documentation or proximal evidence of an acute intracranial bleed from imaging studies not thought to be present on admission. Bradycardia and ventricular tachy- cardia was defined as a HR lower than 60 beats per minute (bpm) and greater than 100 bpm respectively within one hour after a PHE bolus.

a Median.

b Includes any diagnosis documented at a frequency of b2.7%.

male sex. Almost half (45.2%) of the population had a primary diagnosis of septic shock upon admission to the ED (Table 1).

For the primary outcome, 46.5% (n = 34) of patients were initiated on a CVI within 30 minutes following bolus-dose PHE with a median time to initiation of 6.5 minutes. Forty-nine patients (67.1%) received preload expansion with IVF prior to PHE administration with a median of 30.9 mL/kg (Table 2).

For secondary endpoints, PHE was most commonly indicated for peri-intubation hypotension with 52 (71.2%). Evaluation of PHE use re- vealed a median of two boluses (range 1-6) per patient with variable dosing schemes (Table 2). Significant adverse events were documented for 15 (20.5%) patients (Table 3).

Comparison of outcomes between adequately and inadequately fluid challenged patients can be found in (Table 4). Twenty-five (34.2%) vs 48 (65.8%) patients were found to be appropriately fluid challenged with at least 30 mL/kg of crystalloid IV fluids (P = .0048; post hoc power 75.2%). The baseline characteristics between the 2 groups were comparable, with the exception of gender. Less PHE bolus- es (1.5 vs. 2.3 doses, P = .01) administered in the adequately fluid chal- lenged group. Patients in the adequately challenged group were initiated on a CVI within 30 minutes less frequently than the inade- quately challenged group (36% vs. 54%, P = .14; post hoc power 14.4%). At least one hour after PHE was given, mean MAP increased from 56.5 (+-19.9) mmHg to 79.3 (+-21.0) mmHg (P b .05), and mean HR was not significantly increased from 91.4 (+-31.7) bpm to

91.8 (+-25.2) bpm (P = .979).

Table 2

Initiation of CVI following bolus-dose PHE, and the prior Volume expansion Primary end point: n = 73 Median (IQ1-IQ3)

  1. Statistical analysis

Patients initiated on CVI infusion within

30 minutes following first PE dose

Indication for PHE

34 (46.5%) 6.5 (3-13.5) min

A convenience sample of all patients meeting the inclusion criteria for an 18-month period was evaluated. Numerical de-identified discrete variables were analyzed using descriptive statistics. Baseline character- istics and outcomes of patients that were initially adequately preload expanded with at least 30 mL/kg of IV fluids were compared with

those patients that received less than 30 mL/kg of IV fluids using a ?2

Peri-intubation hypotension 52 (71.2%) Bridge to continuous vasopressor infusion 11 (15.1%) Acute hypotension 10 (13.7%) PHE dosing

Patients receiving multiple doses of PHE 39 (53.4%) 2 (1-3)

Single PE dose 100 (100-200) ug

Cumulative PE dose 200 (100-400) ug

Weight-based Cumulative PE dose 2.39 (1.47-5.2) ug/kg

or Fisher exact test where appropriate. Ten percent of the primary out- come data was reviewed by a coinvestigator to determine the interrater variability resulting in 100% agreement; therefore, a Kappa statistic was

not performed.

Number of orders for a single PE dose of 1000 mcg

Preload expansion

Weight-based volume of IVF given prior to PHE

10 (13.7%)

49 (67.1%) 30.9 (11.5-35.14) ml/kg

  1. Results

A total of 98 patients were identified to have at least one document- ed order and administration of bolus-dose PHE, and 73 patients met in- clusion criteria for analysis. The median age was 65 years, with 60.3%

Total volume of IVF given prior to PHE 49 (67.1%) 1000 (0-2000) ml

Type of CVI initiated within 30 minutes (n = 34)

Norepinephrine 31 (91%)

Epinephrine 1 (3%)

Phenylephrine 1 (3%)

Vasopressin 1 (3%)

Intravenous Fluids (IVF), Continuous Vasopressor Infusions (CVI), Phenylephrine (PHE).

M.B. Schwartz et al. / American Journal of Emergency Medicine 34 (2016) 24192422 2421

Table 3

Documented serious adverse effects associated with bolus-dose phenylephrine Adverse effect Frequency – n (%)

Reactive hypertension Ventricular tachycardia

6 (8.2%)

2 (2.7%)

initiation of vasoactive agents with the lowest hospital mortality; where-

as, lower fluid volumes and premature vasoactive administration was as-

Bradycardia

7 (9.6%)

sociated with a higher predicted mortality [15]. The approach evaluated

Intracranial bleed/hemorrhage Extravasation

0 (0%)

0 (0%)

in the current study may inadvertently mask an under resuscitated pa-

tient prolonging time to or even amount of preload expansion. While

maximized. Evidence has suggested an interaction between fluids and va- soactive agents on mortality in septic shock, identifying an association be- tween early and sufficient fluid challenge as well as appropriate delay in

  1. Discussion

Following administration of bolus-dose PHE, 34 (46.5%) patients were initiated on a CVI within 30 minutes following the first dose of PHE. Thus, it appears that although bolus-dose PHE in the ED setting may transiently elevate blood pressures, eventually a CVI may be re- quired to sustain normotension.

Twenty-five (34.2%) patients were considered to have received an ade- quate fluid load (with at least 30 mL/kg of IVF) prior to PHE utilization. Early and sufficient preload expansion required less PHE boluses (1.5 vs 2.3) along with a lower rate of CVIs needed within 30 min following bolus- dose PHE. More patients required a CVI following PHE if they were not ad- equately fluid challenged (36% vs. 54%). Although this was not statistically significant (P = .14), this may signify the circumvention of standard ap- proaches to the care of hemodynamically unstable populations, instituting a therapy addressing a number (i.e. BP or MAP) rather than the Underlying etiology of hypotension, and warrant a more focused examination.

Administration of a 30 mL/kg bolus of crystalloid fluids within 30 mi- nutes of sepsis or septic shock identification has been associated with a decrease in patient mortality and ICU admission [14]. Patients identified as fluid responsive may achieve adequate blood pressure elevation and restoration with preload expansion alone without requiring vasopressors. The 2012 Surviving Sepsis Guidelines recommend that vasopressors be administered only once hypotension is found to be persistent despite ad- equate fluid challenge [5]. In fact, early administration of vasopressors fol- lowing the onset of septic shock may be detrimental if preload expansion is incomplete, and may cause reductions in cardiac output as well as hin- der end organ perfusion if intravascular volume and preload are not

Table 4

Comparison patients outcomes based on adequacy of initial Fluid expansion prior to PHE bolus (n = 73)

common practice may involve use of PHE in circumstances of insufficient time or an unknown volume status and thus less pre-intervention volume is implemented. The current evidence suggests practitioners should con- tinue to volume resuscitate after PHE use or postponing procedures until adequate fluid challenge. The elevation in blood pressures seen in re- sponse to vasoactive agents may influence clinicians to utilize less fluids to maximize preload, which may influence patient outcomes.

Adequacy of preload expansion may be a factor in requiring CVI within 30 minutes following bolus-dose PHE. The results of our study suggest that presumptive utilization of bolus dose PHE in the absence of definitive diagnosis of the etiology of hypotension may circumvent a more appropriate, stepwise therapeutic approach. This may result in use of additional therapies that may be unnecessary, as was highlighted in the current study by the higher frequency of vasopressor infusions in those patients not receiving adequate preload expansion. This suggests the presence of a volume responsive hypotension that may not have been optimized upon initial therapeutic approach (i.e. PHE).

In the procedural anesthesia literature, bolus-dose PHE has shown to reverse acute anesthesia-induced hypotension [8-12]. The patterns of utilization of bolus-dose PHE in the ED appears to mirror its use ob- served in other practice areas, primarily being administered peri- procedurally, most commonly surrounding intubation in this setting. However, the etiologies of hypotension across these practice areas may be markedly different. The Hemodynamic response findings of this study were similar to those of Panchal et al. when they reported bolus-dose PHE increased mean systolic and diastolic blood pressures by 20 and 10 mmHg; respectively, with no significant effect on heart rate at 60 minutes after intubation, suggesting that peripheral bolus- dose PHE increases BP when given for peri-intubation hypotension in the ED [13]. Similar to this study these findings could be attributed to the subsequent initiation of vasopressor infusions after PHE.

The limitations of the current study stem from the retrospective na- ture of data collection. We were unable to capture prehospital therapies (IV fluids, vasopressors). In addition, we did not capture the type of line accessed for PHE administration along with alternative fluid resuscita-

Fluid challenge

N30 mL/kg

Fluid challenge P

b30 mL/kg

tion indicators such as central venous Pressure measurements. Data was reliant on nursing documentation which may be limited by its accu- racy. Finally comorbidities were not collected limiting the ability to evaluate fluid decisions or PHE impact on certain populations such as those intolerant to volume or afterload increases.

  1. Conclusion

Baseline characteristics

25 (34.2%)

48 (65.8%)

P = .0048

Age

63.4

66.9

P = .33

Female

6 (24%)

23 (48%)

P = .047

Male

Weight (kg)

19 (76%)

85 kg

25 (52%)

87 kg

P = .70

Septic shock

PHE doses

13 (52%)

19 (39.6%)

P = .31

SBP prior to 1st dose? 82.9 mmHg 76.1 mmHg P = .14 MAP prior to 1st dose? 62 mmHg 55.2 mmHg P = .07 HR after 1st PHE bolus? 96.5 bpm 91.8 bpm P = .45

Cumulative PHE dose? Number of PHE Doses?

200 mg

1.5

300 mg

2.3

P = .35

P = .01

The role of bolus-dose PHE in the ED remains unclear, despite its uti-

lization. Initial preload IVF expansion was found to be significantly dis-

Hemodynamics prior to PHE proportionate, and appears to be associated with an increase number of

CVI administration peri-PHE bolus

phenylephrine bolus doses. The safety of bolus-dose PHE in this study showed adverse cardiac outcomes such as; reactive hypertension, tachycardia, and reflexive bradycardia. Further studies are needed to as-

CVI prior to the 1st PHE bolus

4 (16%) 6 (12.5%) P = .68

sess appropriateness, efficacy, and CVI utilization of bolus-dose PHE in acutely hypotensive patients in the ED.

CVI within 30 min 9 (36%) 26 (54%) P = .14

CVI between 30-60 min CVI between

60 min-24 h

6 (24%) 3 (6.3%) P = .029

3 (12%) 4 (8.3%) P = .61

References

No vasopressor infusion 3 (12%) 10 (20.8%) P = .35

BPM, beats per minute.

* Median.

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