Fever and Hypotension Vs. Frank Septic Shock: Elderly Patients Taking Vasodilators Who Present with Fever and Hypotension Have a Higher Incidence of Negative Blood Cultures. A Retrospective Analysis of 3,726 Patients.

doi:10.21203/rs.3.rs-4396864/v1

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Fever and Hypotension Vs. Frank Septic Shock: Elderly Patients Taking Vasodilators Who Present with Fever and Hypotension Have a Higher Incidence of Negative Blood Cultures. A Retrospective Analysis of 3,726 Patients.

https://doi.org/10.21203/rs.3.rs-4396864/v1

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Background. Septic shock is a leading cause of mortality. Yet, blood cultures are negative in many cases, questioning the diagnosis. In the quest for characterization of “culture negative septic shock”, the impact of chronic vasodilating medications was questioned.

Methods. This was a retrospective analysis of patients with vital signs compatible with septic shock (fever > 37.9 or < 36ºC and systolic blood pressure < 90 mmHg).

Results. The study included 3,726 patients (ages 65 to 90). Of these, 1,382 (37.1%) took chronic vasodilators. This group of patients had a lower rate of positive blood cultures compared to the group that did not receive vasodilators (28.5% vs. 32%; P = 0.026). They were older (median 80 vs. 78 years; P = 0.001), and their background included more cardiovascular diseases (P < 0.001). Their total length of hospital stay was shorter (median 4 vs. 6 days; P < 0.001) yet, they had a higher risk of in-hospital mortality (39% vs. 35.1%; P = 0.019). Taking chronic vasodilators was associated with decreased risk for bacteremia by 16% (P = 0.023). Older age, positive bacterial culture, and chronic vasodilation treatment were independently associated with increased risk for in-hospital mortality by 3% (P < 0.001), 36% (P < 0.001), and 21% (P = 0.009) respectively.

Conclusion. Chronic use of vasodilators amongst elderly patients presenting with fever and hypotension is associated with a higher incidence of negative blood cultures. We suggest these patients exhibit a combination of sepsis and shock rather than frank septic shock.

Sepsis

Septic Shock

Bacteremia

Hypotension

Vasodilating medications

Arterial hypertension.

Septic shock remains a significant cause of death.

Sepsis remains a worldwide critical healthcare condition with morbidity and mortality rates, of about 34% to 46% despite advancements in medical care (1–3). Septic shock, the downhill scenario of severe sepsis, is characterized by circulatory failure and associated metabolic abnormalities which are linked to an even higher mortality risk compared to sepsis alone (4,5). The hallmark of shock is systemic arterial hypotension despite sufficient fluid resuscitation, defined as systolic arterial pressure below 90 mmHg or a mean arterial pressure below 65 mmHg, these values indicate insufficient tissue perfusion, often manifested by persistent elevated serum lactate level exceeding 2 mmol/L (4,6–8). Timely and accurate diagnosis of septic shock is paramount for initiating appropriate interventions and improving patient outcomes (9).

Refractory septic shock, with persistently low blood pressure, remains the main cause of death of patients diagnosed with sepsis (10) and is a frequent cause of emergency room (ER) presentations and intensive care unit (ICU) hospitalizations. Prompt identification and treatment of conditions suspected to be septic shock are pivotal for patients' survival (11). These treatments include wide-range empiric antibiotics, volume expansion with crystalloid solutions and appropriate use of vasoconstrictor agents and mineralocorticoids (12).

However, although sepsis and septic shock are defined as a response to infection, a culprit bacterium may not be isolated in blood cultures in up to 30% of patients presenting with septic shock. This subset of patients also has better survival compared to those with positive blood cultures (13), suggesting that “culture-negative septic shock” might be a distinct clinical entity. In this entity, causes of hypotension are not solely derived from bacterial / bacteremia induced inflammation and may be associated with concomitant medical therapy contributing to hypotension.

Could vasodilating medications contribute to the phenotypic culture-negative septic shock?

Antihypertensive agents mitigate the sympathetic response aiming at chronically averting end-organ damage by reducing cardiac output and/or systemic vascular resistance (14). First-line agents act as vasodilators, targeting either the renin-angiotensin-aldosterone system (RAAS) or the L-type calcium channels (15,16). The use of antihypertensive agents in general and vasodilating agents specifically, could potentially exacerbate hypotension and facilitate patients’ deterioration from a febrile disease or sepsis to a clinical picture of septic shock which may be better described as sepsis and shock. Vasodilating agents, due to their effects on blood pressure regulation and cardiovascular physiology (17), might deprive febrile patients, mainly elderly, of their natural physiologic defense mechanisms, e.g., vasoconstriction.

The aim of the current study: Septic shock or sepsis and shock?

This study aimed to assess the prevalence of negative blood cultures among elderly patients presenting with fever and hypotension to the emergency department, while chronically treated with vasodilating medications versus those who were not treated with such medications. Also, we intended to explore the outcomes of these patients. By this, we intended to enhance our understanding of these medications’ potential impact on the recognition and management of these patients.

Patient population

We included patients aged 65 to 90 years with suspected septic shock (defined as fever above 37.9º C or below 36º C and systolic blood pressure below 90 mmHg) who presented at the ED of a large tertiary medical center. Following approval by the local ethics committee and waiver of informed consent due to the retrospective nature of the study (approval # SMC-0348-23), relevant patients’ characteristics were extracted from their electronic medical records. These records are routinely used for patient diagnosis and therapy and are therefore considered reliable and appropriate for patient data retrieval. Out of 9,194 patients who presented at our ED between January 2015 and December 2022, we excluded 2,250 patients who had missing culture results values or that recorded values were inapplicable. We further excluded 3,218 patients not in the 65 to 90 years old bracket. Our final cohort included 3,726 patients which were divided into two groups: The first group included a total of 1,382 patients that were chronically treated with vasodilator medications (vasodilator group). The second group comprised of 2,344 patients that were not chronically treated with vasodilators (non-vasodilator group). Since patients’ possible bacteremia status was monitored during hospitalization, we defined positive culture results only from cultures taken during the first two days of hospitalization to avoid bias due to potential nosocomial infections. Hence, we considered a patient to have a non-nosocomial positive bacteremia status when there was at least one positive culture result during the first two days from presentation at the ED. This definition was made to meet the accepted criteria of considering a nosocomial infection when detected in patients’ cultures taken within 48 hours from admission (18, 19). We compared patients who had documentation of vasodilator treatment in their chronic medication list (vasodilator group) to those who did not (non-vasodilator group). We assumed that false positive results and contamination rates would be similar across the two groups as both groups were treated at the ED during the same time interval and by the same staff. Figure 1 details our patient consort flow and exclusion diagram.

Statistical analysis

Patients’ baseline demographic and clinical data were retrieved from their Electronic Medical Records (EMR). The primary outcome of this study was prevalence of positive blood cultures, as previously described. Continuous variables were expressed as mean ± standard deviation (SD) if normally distributed, or median with interquartile range (IQR) if skewed. Categorical variables were presented as frequency (%). Continuous data were compared with the student’s t-test when normally distributed, and with a non-parametric Wilcoxon signed-rank test when normality was rejected by a QQ-plot. Categorical data were compared using chi-square or Fisher’s exact tests. Logistic regression was used to analyze the Odds Ratio (OR) of each risk factor of the primary outcome including a univariate model to determine the unadjusted OR, and a multivariate model to control for possible confounders including gender, age, and relevant medical history whenever found to be significantly different between the two patients’ groups on a univariate analysis. An association was considered statistically significant for a two-sided P value of less than 0.05. All analyses were performed using R software version 4.3.0 (R Foundation for Statistical Computing).

The studied cohort had a total of 3,726 patients between the ages of 65 and 90 years who presented to the ED with vital signs compatible with the definition of septic shock. Of these patients, 1,382 (37.1%) were in the vasodilator group, and 2,344 were in the non-vasodilator group (Table 1). The vasodilator group had a significantly lower rate of positive blood cultures compared to the non-vasodilator group (28.5% vs. 32% respectively; P = 0.026). Further, there was no significant difference in the number of cultures taken during the first two days of the hospitalization period between the vasodilator group and the non-vasodilator group (both groups had a median of 6 [IQR = 6] cultures; P = 0.208). There was no significant difference in the male-to-female ratio between the two groups: 1.17:1 male/female ratio in the vasodilator group and 1.25:1 male/female ratio in the control group (P = 0.315). Patients belonging to the vasodilator group were older with a median age of 80 [IQR = 12] years compared to the non-vasodilator group which had a median age of 78 [IQR = 13.25] years; (P = 0.001). The vasodilator group exhibited a markedly higher prevalence of cardiovascular disease (90.3%) in contrast to the non-vasodilator group (69.3%) with a statistically significant difference (P < 0.001). The vasodilator group also exhibited a higher prevalence of metabolic and endocrine diseases when compared to the non-vasodilator group (77.7% vs. 66.6%; P < 0.001). A history of malignancy or hematological disease was not statistically different between the study groups, where 42.8% of the vasodilator group and 40.7% of the non-vasodilator group had a history of malignancy or hematological disease (P = 0.240). Relating to clinical outcomes, the total length of hospital stay was significantly shorter for the vasodilator group in comparison to the non-vasodilator group (median of 4 [IQR = 5] days vs. 6 [IQR = 11] days respectively; P < 0.001) and had a significantly higher risk of mortality during hospitalization (39% vs. 35.1% respectively; P = 0.019).

Table 1

Demographic and Clinical Features – All Patients.
Demographic and clinical attributes	Overall [n = 3,726]	No vasodilators [ n = 2,344]	On Vasodilators [n = 1,382]	P-value
Blood culture workup
Positive blood culture; N (%)	1,145 (30.7)	751 (32)	394 (28.5)	0.026
Blood cultures taken during first 2-days; N (median [IQR])	6 [3, 9]	6 [3, 9]	6 [3, 9]	0.208
Patients Demographics
Age (median [IQR])	79 [72, 85]	78 [71, 84.25]	80 [73, 85]	0.001
Male gender = N (%)	2,047 (54.9)	1,303 (55.6)	744 (53.8)	0.315
Medical Background
Cardiovascular disease; N (%)	2,873 (77.1)	1,625 (69.3)	1,248 (90.3)	< 0.001
Metabolic / endocrine disease; N (%)	2,636 (70.7)	1,562 (66.6)	1,074 (77.7)	< 0.001
Malignancy / hematological disease; N (%)	1,546 (41.5)	955 (40.7)	591 (42.8)	0.240
Clinical Outcomes
Length of hospital stay; days (median [IQR])	5 [3, 11]	6 [3, 14]	4 [2, 7]	< 0.001
In-hospital mortality; N (%)	1,362 (36.6)	823 (35.1)	539 (39)	0.019

Univariate and multivariate logistic regressions for positive blood cultures

The univariate logistic regression analysis results showed that patients in the vasodilator group had significantly lower odds for a positive culture (OR = 0.84, 95% CI [0.73, 0.98]; P = 0.024) (Table 2a). Further, our multivariate logistic regression analysis showed similar results after controlling for possible confounders including age, gender, background cardiovascular disease, metabolic and endocrine disease, and malignancy / hematologic diseases (Table 2b). We incorporated malignancy and hematological diseases into our multivariate model since these are major risk factors for infection and sepsis (20) even though these were not found to be significantly different between study groups in the univariate analysis. The multivariate analysis results revealed that the vasodilator group had a lower probability of a positive culture result with a 16% chance reduction for a positive bacteremia status (OR = 0.84, 95% CI [0.72, 0.97]; P value = 0.022) at presentation in the ED with suspected septic shock. Patients with a clinical background of malignancy were at higher risk of having positive results on bacterial cultures, with a corresponding 20% higher risk of positive culture (OR = 1.20, 95% CI [1.04, 1.38]; P = 0.013). Age, gender, cardiovascular and metabolic / endocrine disease had no significant effect in our multivariate analysis.

Table 2

Positive culture logistic regression analysis
Variable	OR	95% CI	P
(a) Univariate analysis
On vasodilators	0.84	[0.73, 0.98]	0.024
(b) Multivariate analysis
On vasodilators	0.84	[0.72, 0.97]	0.022
Age; each year increment	1	[0.99, 1.01]	0.768
Gender; Male	1.06	[0.92, 1.22]	0.428
Cardiovascular disease background	0.96	[0.79, 1.16]	0.667
Metabolic / endocrine disease background	1.15	[0.97, 1.36]	0.120
Malignancy / hematologic disease background	1.20	[1.04, 1.38]	0.013

In contrast to the relative protective effect of vasodilators on the fate of the blood cultures’ results, our findings show that those patients had a higher risk of mortality. This necessitates an alternative explanation rather than septic shock. Table 3 present a multivariate logistic regression analysis addressing the risk of mortality.

We found that the vasodilator group had a 21% increase in the risk for mortality while hospitalized with a clinically suspected septic shock (OR = 1.21, 95% CI [1.05, 1.4]; P = 0.009). A positive culture during the first two days of hospitalization increased the risk of in-hospital mortality by 36% (OR = 1.36, 95% CI [1.18, 1.57]; P < 0.001), and older age increased the risk of in-hospital mortality by 3% for every one year of age (OR = 1.03, 95% CI [1.02, 1.04]; P < 0.001). The effects of gender, background cardiovascular, metabolic, and endocrine, and malignancy / hematologic diseases on in-hospital mortality were not statistically significant in this multivariate model.

Table 3

Mortality during hospitalization logistic regression analysis
Variable	OR	95% CI	P
On vasodilators	1.21	[1.05, 1.4]	0.009
Positive culture	1.36	[1.18, 1.57]	< 0.001
Age	1.03	[1.02, 1.04]	< 0.001
Gender; Male	1.06	[0.92, 1.21]	0.418
Background Cardiovascular disease	0.85	[0.72, 1.02]	0.086
Background metabolic / endocrine disease	1.01	[0.85, 1.19]	0.936
Background Malignancy / hematologic disease	1.08	[0.94, 1.24]	0.272

A high index of suspicion for septic shock is crucial; therefore, patients presenting with fever and hypotension should be considered as having septic shock until proven otherwise. As real-time, point-of-care identification of bacteremia is still unavailable, such patients should be promptly treated with wide-spectrum, intravenous antibiotics. Nevertheless, other, considerably aggressive management awaits these patients: to provide high-volume fluid resuscitation and catecholamines, central venous catheters are generally inserted. These interventions are associated with significant inconvenience and iatrogenic complications (21, 22). Therefore, potential alternative explanations for hypotension in such patients should always come to attention, especially in elderly patients who are chronically treated by vasodilators for arterial hypertension. Such patients are practically deprived of one of their main physiologic defense mechanisms in the face of lowering blood pressure: vasoconstriction. In this study, we hypothesize that chronic vasodilator usage may explain, in part, the culture-negative septic shock, since these patients present a combination of fever and shock rather than frank septic shock. Such recognition should not deter clinicians from administrating antibiotics for febrile, hypotensive patients but it may be beneficial to consider postponing invasive procedures until the hypotensive effect of the last administered vasodilator subsides. A similar concept was offered by Chua et al.; They found that patients with culture-negative septic shock, who exhibit early clinical improvement, could be considered for early de-escalation of antibiotic therapy without compromising their clinical outcomes. They did not characterize the culture-negative patients regarding chronic use of medications (23). In their metanalysis of 10 studies, involving almost 24,000 patients, Afzai et al. compared the clinical outcomes of culture-positive vs. culture-negative patients and found that there were no significant differences in all-cause mortality, need for mechanical ventilation, hemodialysis and length of ICU stay (24). They did not address potential etiologies for hypotension amongst their culture-negative patients as well, and therefore, it could be argued that other causes for deterioration enhanced the death of patients whose cultures turned to be negative. In our cohort, patients that were chronically treated with vasodilators had higher mortality even though they had a lower incidence of positive blood cultures. This could be ascertained to their older age and their higher prevalence of cardiovascular, metabolic, and endocrine background morbidities. Others addressed potential surrogate markers that potentially could predict positive blood cultures such as procalcitonin levels (25).

In our study patients who were treated with chronic vasodilating medications turned to have a shorter length of hospital stay. This could be ascertained, in part, to their higher rate of in-hospital mortality.

Chronic medications that were found beneficial and life-prolonging in the context of chronic diseases might be associated with the deprivation of patients from their life-saving physiology during acute illness. One such scenario is the case of vasodilating agents. These may be associated with decreased vasoconstriction potential in elderly patients with febrile illness, causing patients to present with fever and hypotension, generally diagnosed as frank septic shock. This association should be in mind of ED and internal medicine physicians while considering the aggressiveness of treatment measures. Further prospective studies should consider the option of waiting for the vasodilating effects to subside.

Limitations

This was a retrospective, single-center study, and therefore, the results may represent a specific patients population and generalization of our results should be done cautiously. Multicentered, prospective, controlled studies may enhance our understanding of the impact of chronic anti-hypertensive and negative inotropic medications on a variety of populations.

Author Contribution

D.B., V.A., I.M., G.M., L.Z.C., I.E., and G.S. all countributed to the design and data curation of the study. D.B., I.E. and G.S did the data analysis and tabels, D.B., V.A., I.M., G.M., L.Z.C., I.E., and G.S wrote the original manuscript and also the finalized manuscript.

Data Availability

Data is provided within the manuscript

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You are reading this latest preprint version

Fever and Hypotension Vs. Frank Septic Shock: Elderly Patients Taking Vasodilators Who Present with Fever and Hypotension Have a Higher Incidence of Negative Blood Cultures. A Retrospective Analysis of 3,726 Patients.

Status:

Version 1

Abstract

Figures

Background

Methods

Patient population

Statistical analysis

Results

Univariate and multivariate logistic regressions for positive blood cultures

Discussion

Conclusions

Limitations

Declarations

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1