In-hospital Mortality Following Treatment With Red Blood Cell Transfusion or Inotropic Therapy During Early Goal-directed Therapy for Septic Shock

A Retrospective Propensity-Adjusted Analysis

Dustin G Mark; John W Morehouse; Yun-Yi Hung; Mamata V Kene; Andrew R Elms; Vincent Liu; Dustin W Ballard; David R Vinson

Disclosures

Crit Care. 2014;18(496)

Abstract and Introduction

Abstract

Introduction We sought to investigate whether treatment of subnormal (<70%) central venous oxygen saturation (ScvO₂) with inotropes or red blood cell (RBC) transfusion during early goal-directed therapy (EGDT) for septic shock is independently associated with in-hospital mortality.

Methods Retrospective analysis of a prospective EGDT patient database drawn from 21 emergency departments with a single standardized EGDT protocol. Patients were included if, during EGDT, they concomitantly achieved a central venous pressure (CVP) of ≥8 mm Hg and a mean arterial pressure (MAP) of ≥65 mm Hg while registering a ScvO₂ < 70%. Treatment propensity scores for either RBC transfusion or inotrope administration were separately determined from independent patient sub-cohorts. Propensity-adjusted logistic regression analyses were conducted to test for associations between treatments and in-hospital mortality.

Results Of 2,595 EGDT patients, 572 (22.0%) met study inclusion criteria. The overall in-hospital mortality rate was 20.5%. Inotropes or RBC transfusions were administered for an ScvO₂ < 70% to 51.9% of patients. Patients were not statistically more likely to achieve an ScvO₂ of ≥70% if they were treated with RBC transfusion alone (29/59, 49.2%, P = 0.19), inotropic therapy alone (104/226, 46.0%, P = 0.15) or both RBC and inotropic therapy (7/12, 58.3%, P = 0.23) as compared to no therapy (108/275, 39.3%). Following adjustment for treatment propensity score, RBC transfusion was associated with a decreased adjusted odds ratio (aOR) of in-hospital mortality among patients with hemoglobin values less than 10 g/dL (aOR 0.42, 95% CI 0.18 to 0.97, P = 0.04) while inotropic therapy was not associated with in-hospital mortality among patients with hemoglobin values of 10 g/dL or greater (aOR 1.16, 95% CI 0.69 to 1.96, P = 0.57).

Conclusions Among patients with septic shock treated with EGDT in the setting of subnormal ScvO₂ values despite meeting CVP and MAP target goals, treatment with RBC transfusion may be independently associated with decreased in-hospital mortality.

Introduction

Early goal-directed therapy (EGDT), when applied to emergency department (ED) patients with septic shock, can reduce mortality compared to standardized resuscitation that targets central venous pressure (CVP), mean arterial pressure (MAP) and urine output goals.^[1] EGDT can be conceptualized as a central venous oxygen saturation (ScvO₂)-guided resuscitation protocol, targeting a goal ScvO₂ of 70% or greater once standardized CVP, MAP and urine output targets have been achieved. ScvO₂ values below the 70% target can be increased with therapies aimed at decreasing oxygen consumption (VO₂), such as mechanical ventilation, sedation and/or pharmacologically induced paralysis, and with therapies aimed at increasing oxygen delivery (DO₂), such as volume expansion, inotropic therapy, red blood cell (RBC) transfusion and vasodilator administration.^[2–5]

Since the landmark EGDT trial,^[1] impressive advances have been reported in reducing sepsis-related mortality with implementation of EGDT-based resuscitation bundles.^[6–10] However, the incremental benefit of the ScvO₂-guided DO₂ augmentation components of these bundles is unclear.^[9,11–14] In particular, the ability of RBC transfusions to augment DO₂ in sepsis appears minimal,^[14–18] and liberal transfusion strategies in high-risk or critically ill patients may result in increased mortality rates,^[19–23] though observational propensity-matched data has suggested an inverse association between RBC transfusion and mortality among patients hospitalized with sepsis.^[15,24] Physiologic studies of inotropic therapy in septic shock have demonstrated heterogeneous individual responses both in terms of global cardiac performance and microcirculatory perfusion, with some studies even suggesting overall harm.^[13,25–30]

Given these uncertain and variable associations, we specifically examined a subset of patients with septic shock, treated in the ED, with documented eligibility for DO₂ augmentation therapies according to an EGDT protocol. Prior research has been limited in this regard since prospective studies of EGDT have reported significantly fewer proportions of patients either eligible for or receiving DO₂ augmentation therapies as compared to the landmark EGDT trial.^[10,31–35] The specific goals of this investigation were to examine associations between EGDT-recommended DO₂ augmentation therapies (RBC transfusion and inotropic therapy) and in-hospital mortality rates using a propensity-adjusted analysis. We hypothesized that treatment with DO₂ augmentation therapies would be associated with improved in-hospital survival when adjusting for severity of illness and comorbidities.

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Table 1. Patient characteristics and variables according to ScvO ₂-guided therapies
	Entire cohort (n = 572)	Inotrope administered (n = 238)	RBCs transfused (n = 71)	No intervention (n = 275)
Demographics and comorbidities
Age, years	73 (62–82)	76 (65–83)	70 (61–81)	71 (60–81)
Female (%)	46.7	47.1	46.5	46.2
Race
White (%)	57.9	57.1	49.3	59.6
Asian (%)	13.5	15.5	14.1	12.0
Hispanic (%)	12.9	11.8	14.1	13.5
African-American (%)	8.2	7.6	14.1	7.6
Other (%)	7.5	8.0	8.4	7.3
Ischemic heart disease (%)	31.3	30.7	38.0	30.2
Congestive heart failure (%)	36.4	39.5	32.4	34.2
Chronic lung disease (%)	34.1	30.7	26.7	38.9
Diabetes (%)	34.8	34.4	26.7	37.1
HIV/AIDS (%)	0.9	0.4	1.4	1.1
Malignancy (%)	14.9	12.2	32.4	13.1
Rheumatologic disease (%)	6.3	5.0	9.9	6.5
Elixhauser score	16 (8–23)	16 (10–22)	19 (11–28)	15 (7–23)
Initial presenting variables
Systolic blood pressure, mm Hg^a	109 (92–129)	109 (92–129)	102 (86–113)	112 (93–132)
Diastolic blood pressure, mm Hg^a	63 (52–76)	63 (50–76)	56 (44–68)	64 (53–77)
Heart rate, bpm^a	109 (92–125)	108 (91–124)	118 (99–130)	108 (90–124)
Shock index^a	1.0 (0.8–1.2)	1.0 (0.8–1.2)	1.1 (0.9–1.4)	1.0 (0.8–1.2)
Initial serum lactate, mmol/L^b	4.4 (3.0–6.2)	4.5 (3.2–6.3)	4.4 (3.6–7.7)	4.3 (2.8–6.0)
Positive blood cultures (%)	35.3	35.7	49.3	32.4
EGDT treatment period variables
Fluid administered by 6 hours, liters	4.0 (3.0–5.0)	4.0 (3.0–5.1)	4.1 (3.0–5.0)	4.0 (2.6–5.0)
Peak CVP, mm Hg^b	16 (13–21)	16 (13–21)	15 (12–19)	16 (13–22)
Hemoglobin nadir, g/dL^b	11.4 (9.5–13.2)	12.1 (10.3–13.6)	7.9 (7.1–8.8)	11.3 (10.0–13.1)
Antibiotic therapy within one hour (%)	93.4	94.5	95.8	91.6
Mechanical ventilation (%)^b	32.5	32.4	31.0	32.7
Vasopressor administration (%)^b	58.6	72.7	62.0	46.2
Initial ScvO₂, percent^b	63 (55–69)	62 (55–69)	61 (55–68)	64 (57–69)
Final ScvO₂, percent^b	68 (61–73)	68 (62–73)	70 (60–75)	67 (61–72)
Final ScvO₂ > 70% (%)	43.5	46.6	51.3	39.4
Lactate clearance, percent per hour^b	8.4 (4.5–12.9)	8.3 (4.2–12.6)	9.5 (3.6–13.0)	8.3 (4.5–13.0)
Lactate clearance >5% per hour (%)	72.5	72.5	72.4	71.8
mSOFA score at 6 hours	4 (3–6)	5 (4–7)	5 (3–6)	4 (2–6)
eSAPS 3 score	50 (44–57)	52 (46–58)	52 (45–59)	48 (43–55)
Post-treatment variables
mSOFA score at 24 hours	5 (3–7)	5 (4–7)	5 (3–7)	4 (3–6)
In-hospital mortality (%)	20.5	22.7	18.3	19.3

Continuous values are presented as median values with interquartile ranges in parentheses. Dichotomous variables are presented as percentages. ^aAt initial emergency department presentation; ^bwithin the first six hours from shock recognition (time zero). ScvO₂, central venous oxygen saturation; RBC, red blood cells; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome; mm Hg, millimeters mercury; bpm, beats per minute; EGDT, early goal-directed therapy; CVP, central venous pressure; g/dL, grams per deciliter; mSOFA, modified sequential organ failure assessment score; eSAPS, electronic simplified acute physiology score.

Table 2. Propensity score adjustment among patients eligible for RBC transfusion during EGDT
	RBCs transfused (n = 71)	No RBCs transfused (n = 108)	P value (unadjusted)	P value (adjusted)
Demographics and comorbidities
Age, years	70 (61–81)	72 (60–84)	0.78	0.84
Female (%)	46.5	50.0	0.65	0.83
Race			0.56	0.45
White (%)	49.3	53.7
Asian (%)	14.1	13.9
Hispanic (%)	14.1	14.8
African-American (%)	14.1	7.4
Other (%)	8.4	10.2
Ischemic heart disease (%)	38.0	28.7	0.19	0.38
Congestive heart failure (%)	32.4	31.4	0.90	0.67
Chronic lung disease (%)	26.7	25.9	0.90	0.87
Diabetes (%)	26.7	40.7	0.06	0.90
HIV/AIDS (%)	1.4	0.9	0.77	0.71
Malignancy (%)	32.4	15.7	0.01	0.93
Rheumatologic disease (%)	9.9	6.5	0.41	0.51
Elixhauser score	19 (11–28)	16 (9–24)	0.05	0.95
Initial presenting variables
Systolic blood pressure, mm Hg^a	102 (86–113)	107 (92–127)	0.05	0.90
Diastolic blood pressure, mm Hg^a	56 (44–68)	59 (50–70)	0.51	0.54
Heart rate, bpm^a	118 (99–130)	109 (90–123)	0.02	0.21
Shock index^a	1.1 (0.9–1.4)	1.0 (0.8–1.2)	0.001	0.27
Shock index ≥1.0	74.6	51.9	0.003	0.11
Serum lactate, mmol/L^b	4.4 (3.6–7.7)	4.3 (2.5–5.7)	0.10	0.74
Positive blood cultures (%)	49.3	34.2	0.05	0.73
EGDT treatment period variables
Fluid administered by 6 hours, liters	4.1 (3.0–5.0)	4.0 (3.0–5.7)	0.37	0.48
Peak CVP, mm Hg^b	15 (12–19)	16 (13–22)	0.02	0.57
Hemoglobin nadir, g/dL^b	7.9 (7.1–8.8)	9.2 (8.5–9.5)	<0.001	0.47
Inotropes (%)	16.9	37.0	0.005	0.36
Antibiotic therapy within one hour (%)	95.8	93.5	0.52	0.40
Mechanical ventilation (%)^b	31.0	33.3	0.74	0.74
Vasopressor administration (%)^b	62.0	64.8	0.70	0.60
Initial ScvO₂, percent^b	61 (55–68)	63 (55–69)	0.97	0.87
Final ScvO₂, percent^b	70 (60–75)	67 (61–71)	0.51	0.36
Final ScvO₂ > 70% (%)	51.3	39.1	0.12	0.16
Change in ScvO₂, percent	7 (−2–12)	5 (−4–12)	0.54	0.34
Lactate clearance, percent per hour^b	9.5 (3.6–13.0)	8.5 (3.9–12.0)	0.13	0.09
Lactate clearance ≥5% per hour (%)	72.4	66.5	0.43	0.28
mSOFA score at 6 hours	5 (3–6)	5 (3–7)	0.41	0.94
eSAPS 3 score	52 (45–59)	50 (44–57)	0.35	0.89
Post-treatment variables
mSOFA score at 24 hours	5 (3–7)	5 (4–7)	0.38	0.85
In-hospital mortality (%)	18.3	19.4	0.85	0.12

A subgroup analysis was conducted among patients with a hemoglobin nadir less than 10 g/dL during EGDT. Unadjusted P values are reported for the observed variables based on whether RBC transfusion was administered for an ScvO2 less than 70%. Adjusted P values are based on bivariate regression analyses comparing the propensity score (for RBC transfusion) and each variable. Continuous values are presented as median values with interquartile ranges in parentheses. Dichotomous variables are presented as percentages.
^aAt initial emergency department presentation; ^bwithin the first six hours from shock recognition (time zero). RBC, red blood cells; EGDT, early goal-directed therapy; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome; mm Hg, millimeters mercury; bpm, beats per minute; CVP, central venous pressure; g/dL, grams per deciliter; ScvO₂, central venous oxygen saturation; mSOFA, modified sequential organ failure assessment score; eSAPS, electronic simplified acute physiology score.

Table 3. Propensity score adjustment among patients eligible for inotropic therapy during EGDT
	Inotropes (n = 186)	No inotropes (n = 207)	P value (unadjusted)	P value (adjusted for propensity score)
Demographics and comorbidities
Age, years	76 (67–84)	72 (61–81)	0.01	0.85
Female (%)	46.8	44.9	0.74	0.58
Race			0.45	0.47
White (%)	58.6	62.3
Asian (%)	15.1	11.6
Hispanic (%)	11.8	12.6
African-American (%)	6.4	8.2
Other (%)	8.0	5.3
Ischemic heart disease (%)	31.7	30.0	0.38	0.96
Congestive heart failure (%)	39.8	37.2	0.60	0.91
Chronic lung disease (%)	32.2	42.5	0.04	0.49
Diabetes (%)	34.4	34.8	0.94	0.29
HIV/AIDS (%)	0.5	1.0	0.63	0.66
Malignancy (%)	10.8	12.1	0.68	0.73
Rheumatologic disease (%)	4.8	6.3	0.54	0.57
Elixhauser score	16 (8–21)	15 (7–23)	0.64	0.38
Initial presenting variables
Systolic blood pressure, mm Hg^a	111 (94–130)	113 (95–132)	0.57	0.23
Diastolic blood pressure, mm Hg^a	65 (51–80)	66 (54–78)	0.51	0.31
Heart rate, bpm^a	108 (92–124)	108 (90–125)	0.80	0.50
Shock index^a	1.0 (0.8–1.2)	1.0 (0.8–1.1)	0.85	0.94
Shock index ≥ 1.0	52.7	50.2	0.63	0.74
Serum lactate, mmol/L^b	4.6 (3.4–6.2)	4.4 (3.0–6.2)	0.22	0.47
Positive initial blood cultures (%)	34.4	31.9	0.60	0.40
EGDT treatment period variables
Fluid administered by 6 hours, liters	4.0 (3.0–5.0)	3.5 (2.5–5.0)	0.03	0.34
Peak CVP, mm Hg^b	16 (13–20)	17 (13–22)	0.27	0.45
Hemoglobin nadir, g/dL^b	12.7 (11.6–14.0)	12.2 (10.9–13.7)	0.04	0.11
RBC transfusion (%)	0	0	n/a	n/a
Antibiotic therapy within one hour (%)	95.2	90.8	0.10	0.11
Mechanical ventilation (%)^b	30.6	34.3	0.44	0.58
Vasopressor administration (%)^b	71.5	42.5	<0.001	0.31
Initial ScvO₂, percent^b	62 (55–70)	64 (57–69)	0.44	0.07
Final ScvO₂, percent^b	68 (63–72)	68 (61–73)	0.29	0.62
Final ScvO₂ > 70% (%)	44.4	42.3	0.68	0.80
Change in ScvO₂, percent	5 (−2–13)	3(−4–10)	0.16	0.06
Lactate clearance, percent per hour^b	8.2 (4.8–13.0)	8.5 (4.8–13.6)	0.40	0.38
Lactate clearance ≥5% per hour (%)	74.1	74.2	0.98	0.89
mSOFA score at 6 hours	5 (4–6)	4 (2–6)	<0.001	0.51
eSAPS 3 score	52 (46–58)	48 (43–55)	0.02	0.71
Post-treatment variables
mSOFA score at 24 hours	5 (4–7)	4 (3–6)	0.001	0.21
In-hospital mortality (%)	23.7	18.8	0.24	0.41

A subgroup analysis was conducted among patients with a hemoglobin nadir of 10 g/dL or greater during EGDT. Unadjusted P values are reported for the observed variables based on whether inotropic therapy was administered for an ScvO2 less than 70%. Adjusted P values are based on bivariate regression analyses comparing the propensity score (for inotropic therapy) and each variable. Continuous values are presented as median values with interquartile ranges in parentheses. Dichotomous variables are presented as percentages.
^aAt initial emergency department presentation; ^bwithin the first six hours from shock recognition (time zero). ; EGDT, early goal-directed therapy; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome; mm Hg, millimeters mercury; bpm, beats per minute; CVP, central venous pressure; g/dL, grams per deciliter; RBC, red blood cells; ScvO₂, central venous oxygen saturation; mSOFA, modified sequential organ failure assessment score; eSAPS, electronic simplified acute physiology score

Table 4. Multiple regression and propensity score adjusted odds ratio of in-hospital mortality according to treatment with red blood cell (RBC) transfusion or inotropic therapy during early goal-directed therapy (EGDT)
Odds ratio of in-patient mortality	RBC transfusion	P value	Inotrope therapy	P value
Unadjusted (95% CI)	0.93 (0.52–1.66)	0.80	1.33 (0.92–1.92)	0.12
Multivariate regression adjusted (95% CI)	0.58 (0.29–1.18)	0.14	1.10 (0.70–1.73)	0.68
Propensity score (continuous) adjusted (95% CI)	0.42 (0.18–0.97)	0.04	1.16 (0.69–1.96)	0.57
Propensity score (quintile) adjusted (95% CI)	0.46 (0.21–1.04)	0.06	1.21 (0.77–1.91)	0.41

Multivariate logistic regression analysis of the entire cohort was conducted, followed by propensity score adjusted analyses according to the subgroup of hemoglobin nadir during the first six hours of EGDT treatment; patients with a hemoglobin less than 10 g/dL were included in the analysis of RBC transfusion and patients with a hemoglobin of 10 g/dL or greater were included in the inotrope therapy analysis. Standard error and 95% confidence interval (CI) calculations in the regression analyses are adjusted for clustering by hospital.