Article, Ultrasound

Towards a less invasive approach to the early goal-directed treatment of septic shock in the ED

a b s t r a c t

Introduction: early goal-directed therapy in septic shock defined by Rivers et al was proven to reduce mortality and validated by observational studies. However, criticism is centered in particular on the early requirement of a Central venous catheter and on central venous pressure as an indicator of volume responsiveness. The present study is a pivotal study to investigate the reliability of a less invasive approach, which uses Inferior vena cava and Lung ultrasounds (US) to guide the infusion of fluids and Lactate clearance to monitor tissue perfusion.

Methods: We enrolled 51 patients with septic shock. As a marker of preload optimization, we measured IVC collapse in place of CVP and Serum lactate clearance in place of Central venous oxygen saturation as a marker of tissue perfusion. As outcomes, we considered the accomplishment of the noninvasive EGDT goals, the number of patients treated without the need of a CVC, the amount of fluids administered in the first 6 hours, the development of pulmonary edema, and the overall mortality rate.

Results: Inferior vena cava US evaluation resulted feasible in 92% of patients. Lung US was performed in 100% of cases. In the first 6 hours, only 61.7% of patients received a CVC, an average of 5.5 L of crystalloids were administered, and only 4 patients developed clinical overt pulmonary edema. Mortality was 34% at 28 days and 38.3% at 60 days.

Conclusions: Our approach to resuscitation in septic shock appears feasible in the emergency department and needs further study with a randomized controlled trial.

(C) 2014

Introduction

Severe sepsis and septic shock are a growing cause of mortality among hospitalized patients. Their incidence is increasing due to the aging of the population and the longer survival of frail patients with severe multiple pathologies [1-3].

Although not all septic patients are admitted through the emergency department (ED), many of them do, and there is consistent evidence that care delivered in the ED may have a significant impact on prognosis [4-9].

? Authors’ contributions: DC conceived the study, participated in the design, coordinated the study, and wrote the first draft of the study; FC participated in the design of the study, collected clinical data, and helped draft the study; SP participated in the design of the study, performed descriptive statistics, helped draft the study, and collected clinical data; VT participated in the design of the study and collected clinical data; AV participated in the design of the study and collected clinical data; LM participated in the design of the study and collected clinical data; MC participated in the design of the study and collected clinical data; and DB participated in the design of the study and collected clinical data. All authors read and approved the final manuscript.

?? The authors declare that they have no conflict of interest.

* Corresponding author.

E-mail address: [email protected] (D. Coen).

The therapeutic approach to severe sepsis and septic shock pursues 2 main objectives: (i) early identification of the septic source and its removal whenever possible, in conjunction with prompt antibiotic therapy [10]; and (ii) early and adequate replacement of an effective circulating volume and improvement of tissue perfusion to prevent or reduce organ failure [11,12].

Since 2004, international guidelines for the treatment of severe sepsis and septic shock have been issued under the auspices of the Surviving Sepsis Campaign [13]. Following these guidelines, all patients should be treated according to the Early goal-directed therapy , which was first proven effective in 2001 by Rivers et al [14] who documented a 16.5% absolute decrease in in-hospital mortality for the intervention group. This advantage was maintained at 28 and 60 days [14].

Early goal-directed therapy consists in the application of a bundle of interventions that are performed following a defined algorithm during the first 6 hours of treatment of patients in septic shock. Early goal-directed therapy includes the administration of fluid boluses until a central venous pressure (CVP) of 8 to 12 mm Hg has been reached, followed if necessary by the use of vasopressors aiming at a mean arterial pressure (MAP) at least 65 mm Hg. If a central venous oxygen saturation at least 70% is not reached, red blood cell

http://dx.doi.org/10.1016/j.ajem.2014.02.011

0735-6757/(C) 2014

(RBC) transfusions to obtain a hematocrit more than 30% or inotropes are added [14].

Despite subsequent observations supporting the efficacy of the protocol suggested by Rivers et al [5,7,8,15-18], the implementation of this practice is incomplete, and numerous barriers to its diffusion in the ED have been identified [6,19-24]. The need for early CVC placement to measure CVP and ScvO2 is one of the aspects which have been most frequently criticized [25-27]. Moreover, the choice of guiding volume replacement with CVP has itself been disputed because this parameter has not proven reliable to predict response to volume replacement [27-30]. Dynamic physiologic parameters such as Pulse pressure variation, Brachial artery peak velocity, and inferior vena cava collapsibility have been proposed as more useful alternatives [31-33]. Lastly, it has been recently shown that lactate clearance, which can be determined on peripheral venous or arterial blood, is not inferior to ScvO2 as a marker of tissue perfusion and overall prognosis [34-38]. With these premises and because EGDT was proven useful as a bundle of interventions, whereas the relevance of each of its components is unknown, we believe that there is room to modify some of its steps towards a “less invasive” and more widely applicable protocol to treat patients with septic shock during the first hours of stay in the ED. In particular, we think that CVC placement could be spared in the phase of fluid challenge and volume replenishment, thus allowing EGDT to be initiated quickly and without the risk of side effects inherent in this maneuver. Therefore, we have performed a prospective single-center observational study based on the US measurement of inferior vena cava inspiratory collapsibility (?IVC) in place of CVP as an indicator of cardiac preload and indirectly as a predictor of fluid response to volume challenge [31-33,39,40]. Lung ultrasound (US) was contemporarily used for early identification of pulmonary fluid overload [41-43]. Moreover, we used blood lactate clearance as an indicator of tissue perfusion to reduce the need for early placement of a CVC, which would be required if SvcO2 were measured. To be representative of the “real-world” epidemiology of most ED, we admitted a heterogeneous cohort of patients including patients with active cancer and immunosuppression, which would

have been excluded in the original work by Rivers et al [14].

This study has been conceived of as a feasibility study and as a premise to possible randomized studies needed to demonstrate whether a less invasive approach is not inferior to the classic protocol.

Methods

A total of 51 consecutive patients with septic shock were enrolled at a major metropolitan ED over a 12-month period. The protocol was approved by the institutional review board, and all patients provided informed consent. Patients were included when, in a clinical setting of proven or suspected infection, they had at least 2 criteria for systemic inflammatory response syndrome (white blood cells, N 12,000/mm3 or b 4000/mm3; body temperature, b 36?C or N 38?C; respiratory rate, N 20/minute or PaCO2 b 32 mm Hg; and heart rate, N 90/min), and their MAP was less than 65 mm Hg after a fluid challenge of 20 mL/kg of crystalloids (defined as overt septic shock). Patients were also admitted when a first lactate measurement was more than 4 mmol/L irrespective of blood pressure values (defined as cryptic shock). Patients were excluded if they were less than the age of 18 years, were pregnant, had a history of severe tricuspidal regurgitation or pulmonary hypertension, had a “do not resuscitate” order issued, or presented with myocardial infarction or pulmonary edema. Patients for whom IVC evaluation was not possible (4 of the original 51 patients) were excluded after the initial enrollment. All patients entered a protocol, which required the following interventions to be achieved within the first hour from admission: measurement of urinary output and blood lactate, sampling of 2 sets of hemocultures (and other clinically relevant cultures), administration of oxygen (including noninvasive or invasive ventilation when appropriate), and

adequate wide spectrum antibiotics following the hospital guidelines based upon local bacterial epidemiology. After the initial bolus of crystalloids, which was required as an inclusion criteria before admitting hypotensive patients to the study, crystalloids were administered in further 500 mL boluses as needed to reach an ?IVC between 30% and 50%, unless a MAP at least 65 mm Hg was reached. The ?IVC was calculated according to the following equation [(Dmax – Dmin) / Dmax] x 100, where Dmax is the US measured maximum diameter of the IVC, and Dmin is the minimum diameter. Inferior vena cava was measured in the supine position, with a sector probe from a subcostal view, 2 cm distally from the right atrium. Lung US was also performed after each bolus of fluids to monitor subclinical signs of Lung fluid overload. According to international recommenda- tions, lung US was performed dividing each side of the chest wall in 4 regions and scanning all the resulting 8 regions (Fig. 1). A positive chest region was defined by the presence of 3 or more B lines in a longitudinal plane between 2 ribs. Two or more positive regions bilaterally were considered a marker of interstitial syndrome [41]. When lung US showed the de novo appearance of interstitial syndrome, our protocol required that an echocardiography be performed, and a specialist in intensive care be involved in the planning of subsequent treatment.

Echocardiography was performed in order to identify cardiogenic causes that could contribute to hypotension or persistent hypoperfu- sion (sepsis-induced cardiomyopathy and preexistent ischemic or valvular cardiomyopathy) and to help differentiate cardiogenic pulmonary edema from Acute respiratory distress syndrome . A noradrenaline or high-dose dopamine infusion was started when ?IVC reached 30%, and MAP was still less than 65 mm Hg or when 3 L of crystalloids had been administered without reaching the arterial pressure goal (MAP >=65 mm Hg). Inotropes were used when lactate clearance was not at least 10% at 2 hours. On a subsequent revision of the study protocol, the use of high-dose dopamine was amended according to the new Surviving sepsis campaign guidelines. As a result, only 2 patients (on total 25 treated with vasopressors)

have been treated with high-dose dopamine.

There were no protocol directives as to the use of RBC transfusions, but they were generally administered according to our guidelines for critical patients.

Lactate was measured on admission and then at 2 and 6 hours. A Positive lactate clearance was considered as at least 10% reduction in lactate value [(lactateinitial – lactatet2/6 )/ lactateinitial] x 100, where

Fig. 1. Chest regions defined by the international-acknowledged definition. Each side of the chest consists in 4 regions named 1 to 4. Regions 1 and 2 denote the upper anterior and lower anterior chest areas. Regions 3 and 4 denote the upper lateral and basal lateral chest areas. PSL, parasternal line; AAL, anterior axillary line; PAL, posterior axillary line [41].

lactateinitial was measured at the time of inclusion and lactatet2/6 at 2 and 6 hours.

Our protocols did not indicate to insert a CVC to monitor CVP or ScvO2 but stated to position a CVC only when indicated to infuse vasopressors or to secure an adequate venous access.

Fig. 2 shows an algorithm of the protocol adopted in the study.

All the operators that performed US were either certified by the ultrasonography board of the Italian Society of Emergency medicine (SIMEU) or the Italian Society of Ultrasound in Medicine or had undergone specific training in emergency US (a 2-day course and practical training under supervision following SIMEU directives).

A MyLab Five (Esaote, Florence, Italy) US machine with a convex

2.5 to 6.6 MHz and a sector 2 to 2.5 MHz probes was used.

Results

In 4 of the initial 51 patients (7.8%), an adequate view of the IVC could not be achieved, and they were excluded by the study.

Of the 47 patients who were included, 34 were hypotensive after a fluid challenge of at least 20 mL/kg crystalloids (“overt septic shock”), and 13 were normotensive but had lactates more than 4 mmol/L at the first measurement (“cryptic shock”).

Table 1 describes the general characteristics of the population. Table 2 shows the interventions performed and the goals achieved in the present study. More than one-third of patients were treated without a CVC (10/34 with overt shock and 8/13 with cryptic shock). The mean time to CVC placement was about 2 and one-half hours. Of 29 patients who received a CVC, 23 were treated with vasopressors, whereas 6 received it to ensure a suitable venous access.

The hemodynamic goal of a CVP of 8 to 12 mm Hg suggested by Rivers et al [14] corresponds approximately to an ?IVC between 30% and 50%. During the course of treatment, 46 of the 47 patients (97.8%) reached either a goal of ?IVC between 30% and 50% or a MAP at least 65 mm Hg. More in detail, 34 of 47 patients reached an ?IVC between 30% and 50%, and of the remaining 13 patients who did not reach the ?IVC goal, 12 had in the meantime reached a goal of MAP at least 65 mm Hg. Most of these patients belonged to the group in which, as stated in the methods section, a noradrenaline drip was started when 3 L of crystalloids had been administered without reaching the goal of a MAP at least 65 mm Hg. Compared with their counterparts who reached both the MAP and the ?IVC goal, these patients received a similar amount of fluids (5.2 +- 1.4 L vs 5.2 +- 2.7 L) but were more often treated with noradrenaline (58.3% vs 46.7%) and had a higher overall mortality (58% vs 33%). At the sixth hour, a MAP at least 65 mm Hg was reached in 42 (89.4%) of 47 patients. Of the 5 patients who did

Yes

No

Goal achieved

Inotro pic agents

? 10%

< 10%

? 65 mmHg

Lactate clearance ?

Vasopressors

< 65

mmHg

MAP

< 30%

Crystalloids

> 50%

?IVC #

Hospital admission

ICU referral

Supplemental Oxygen

IVC = Inferior Vena Cava; ?IVC = inferior vena cava collapsibility Index (see text for further explanation); CVP = Central Venous Pressure; MAP = Mean Arterial Pressure; ICU = Intensive Care Unit.

Fig. 2. The “less invasive” EGDT protocol applied in the present study. As compared with the EGDT protocol of Rivers et al [14], in this study, ?IVC (#) is used instead of CVP as a marker of endovascular filling, and in addition, the serum lactate clearance (?) is used instead of ScvO2 to monitor tissue perfusion (see text for further explanation).

Table 1

Baseline characteristics of participants

Patients (N = 47) a

Discussion

The last decade witnessed 2 significant breakthroughs in the

Age (y) 70.2 [+- 15.2]

Sex (%)

Male 53.2

Female 46.8

APACHE II score 20.2 [+- 5.6] b

SOFA score 7.1 [+- 2.9] c

Comorbidities (%)

  • Heart failure 25.0
  • CAD 19.2
  • COPD 18
  • Diabetes 23.8
  • Liver failure 20.9
  • Neurologic problems 25.0
  • Chronic renal failure 5.8
  • Immunosuppression 21.2
  • Active cancer 35.3

Criteria for inclusion (%)

  • Cryptic shock d 27.6
  • Overt shock d 72.3

Vital signs and lactates at inclusion

  • MAP 60.4 [+- 13.4]
  • Heart rate 101.9 [+- 24.4]
  • Lactates (mmol/L) 4.6 [+- 3.3]

Source of infection (%)

  • Lung 34.8
  • Urinary apparatus 30.4
  • Abdomen 28.3
  • Soft tissue 2.2
  • Other 4.3

Values are given as the mean and standard deviation (SD), unless otherwise indicated. Abbreviations: SOFA, Sequential Organ Failure Assessment score; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease.

a Four patients from the original 51 had inadequate IVC US and were excluded from the study.

b n = 44 (no. is smaller than the group size because of missing values).

c n = 41 (no. is smaller than the group size because of missing values).

d Cryptic shock is defined by blood lactate more than 4 mmol/L and MAP at least 65 mm Hg; overt shock is defined by MAP less than 65 mm Hg irrespective of blood lactate level, see also the text.

approach to severely septic patients. The first one was the well- acknowledged benefit of an early and adequate antibiotic treatment. A widely cited study by Kumar et al [10] has shown that every hour of delay in antibiotic treatment after the recognition of hypotension is associated with a 7.6% higher mortality.

The second was the development of EGDT, which reduced the relative risk of in-hospital mortality of approximately 30% in a randomized controlled study by Rivers et al [14]. This study has since become the reference work in the literature and a landmark for the guidelines produced by the Surviving Sepsis Campaign initiative [13,14]. Although EGDT is suggested by international guidelines as the standard approach to patients with septic shock, its efficacy has been proven by one single-center randomized clinical trial, and its applicability in the typical EDs around the world has been questioned by many authors. The early invasiveness of the EGDT approach, which requires a CVC to be placed on every patient to measure CVP and monitor ScvO2, is one of the aspects of this protocol, which has been subject to debate and that puts a de facto strong barrier to its breakthrough in the real world of the EDs and an even stronger one in

general medicine or surgery wards [6,19-24].

Polls and observational studies have largely demonstrated that EGDT is not practiced or not considered as easily implementable in many EDs through different countries [21-25]. For example, in a 2004 survey among US academic emergency medicine physicians, only 7% declared that they applied EGDT as their standard of treatment [6]. Moreover, a questionnaire distributed among American critical care nurse managers revealed that for patients in septic shock, a CVC would be inserted in only approximately 40% of cases [19]. Lastly, in 2010, Mikkelsen et al [20] showed, in an observational study conducted in a major academic American ED, that severe sepsis patients had EGDT initiated only 58% of the time, and that it was completed in slightly over a half of the patients for which it had been initiated.

Table 2

Interventions, hemodynamic goals, and outcomes

not reach a MAP at least 65 mm Hg after 6 hours of treatment, 4 had

received an adequate amount of fluids as confirmed by an ?IVC between 30% and 50% and had been subsequently started on vasopressors.

In conclusion, we were able to reach an adequate volume replenishment in all but 1 patient who needed fluid resuscitation for a MAP less than 65 mm Hg. The amount of fluids administered during the first 6 hours was on average 5.5 L (Table 2). The goal of a lactate clearance at least 10% was reached in 70.3% of cases.

With lung sonography, we recorded a US pattern of interstitial syndrome in 13 (27.7%) of 47 patients. In 4 of these cases, this pattern was already present at the time of enrollment and was considered clinically nonspecific, whereas in the remaining 9 cases, it appeared at some point during treatment. This US finding was considered as a preclinical sign of pulmonary fluid overload, and further investigations were ordered (ie, echocardiography) to guide subsequent treatment. In 3 of 9 cases, a reduced cardiac output was identified by echocardiog- raphy, and inotropes were started under supervision of a cardiologist or intensive care unit specialist. In the remaining 6 cases, fluid adminis- tration was reduced, and vasopressors were started.

On 47 patients treated, we observed 4 cases of clinically overt pulmonary edema. Two of these patients required noninvasive ventilation, one required endotracheal intubation, and the fourth died in the ED.

Overall mortality was 34% at 28 days and 38.3% at 60 days. Mortality at 28 days was 38.2% for septic shock with hypotension and 23% for cryptic shock. Mortality at 60 days was 44.1 for septic shock with hypotension and 23% for cryptic shock.

Patients (N = 47) a

CVC positioned (%) 61.7

Time to CVC (min) 154 [+- 111]

Fluids administered (L) 5.2 [+- 2.3]

Antibiotic within 1 h (%) 63.8

Antibiotic within 6 h (%) 100

Use of vasopressors (%) 53.1

CVP goal (%) NA

?IVC between 30% and 50% (%) b 97.1

MAP >=65 mm Hg (%) 89.4

ScvO2 >=70% (%) NA

US pattern of lung interstitial syndrome (%) 27.7

Clinical overt pulmonary edemac 8.5

Lactate clearance N 10% at 2 h (%)d 62.1

Lactate clearance N 10% at 6 h (%)d 70.3

Positive hemoculturese 31.8

In-hospital mortality for cryptic shock (%) 23.1

In-hospital mortality for overt shock (%) 44.1

Total mortality at 28 d (%) 34

Total mortality at 60 d (%) 38.3

Interventions, goals, and outcomes are calculated at 6 hours from inclusion, unless otherwise indicated.

Values are given as the mean and SD, unless otherwise indicated. Abbreviation: NA, not applicable.

a Four patients from the original 51 had inadequate IVC US and were excluded from the study.

b n = 35; the remaining 12 cases had a MAP 65 mm Hg or more at the sixth hour, and further fluids were not administered.

c Pulmonary edema either cardiogenic or ARDS.

d n = 37; for 8 participants with normal blood lactate, the clearance calculation is NA, and in 2 cases data are missing.

e n = 44 (no. is smaller than the group size because of missing data).

It must also be considered that, in many countries, physicians working in the EDs may not be adequately trained to insert a CVC and that even intensivists and well-trained emergency medicine physi- cians might not feel comfortable at inserting a CVC to monitor the first phase of resuscitation of patients in septic shock when, for different reasons, their clinical “gestalt” tells them that an invasive maneuver might not be necessary [27].

It is in this cultural and pragmatic environment and with the knowledge that focused clinical US is becoming widespread among emergency medicine physicians that we decided to attempt a “less invasive” and more “real-life” conscious approach to the EGDT of sepsis.

In this observational study, we enrolled 51 patients in cryptic or overt septic shock as defined by the international literature with the main objective of monitoring the first phase of patient resuscitation with IVC and lung US, reserving the placement of a CVC to patients for whom a peripheral access was not available, or for those who needed infusion with vasopressors. Our patients had an Acute Physiology and Chronic Health Evaluation II (APACHE II) score similar to that of patients enrolled in the reference study by Rivers et al [14] but differed in comorbidities (more heart and renal failure in the reference study and more active cancer and immunosuppression in our study). Our study was also characterized by a higher percentage of patients with hypotension after the initial fluid challenge, although overall mean lactate values were lower. Comparison with the treatment group in the study by Rivers et al [14] showed a similar mortality despite a somehow lower achievement of hemodynamic goals at 6 hours. With our approach, we were able to spare a CVC insertion to more than one-third of patients, administering an average of 5.2 L of fluids in the first 6 hours with very few patients developing overt pulmonary edema.

A significant minority of our patients (25%) achieved the MAP but not the ?IVC goal. Most of these patients (9/12) belonged to the group in which, as we stated in the methods section, we started a noradrenaline drip when 3 L of crystalloids had been administered without reaching the arterial pressure goal of a MAP at least 65 mm Hg. This is in accordance with the Surviving Sepsis guidelines, which state that “vasopressor therapy is required to sustain life and maintain perfusion in the face of life-threatening hypotension, even when hypovolemia has not yet been resolved.” In fact, below a threshold MAP, autoregulation in critical vascular beds can be lost, and perfusion can become linearly dependent on pressure. These 12 patients could represent a subgroup with specific characteristics (ie, a higher fluid depletion or a more impaired vascular bed regulation), yet their number is too little to infer any conclusion from these data. It could be speculated that patients who do not respond to an initial fluid bolus are at major risk of death or specularly, that the need for noradrenaline associates with a higher mortality.

We are aware that the present study has several limitations: first of

all, it is an observational, single-center study with a limited enrollment of patients. For this reason, it cannot prove the efficacy or the safety of our approach nor its noninferiority to the classic EGDT protocol. Nevertheless, we believe that our results encourage further investigation because we achieved a 28-day and 60-day mortality rate equivalent to that of the reference study by Rivers et al [14] in a population with similar APACHE II score values and with a lower percentage of patients with cryptic shock (27.6% vs 46%, data not shown by Rivers et al [14] but derivable by Table 3 of the original study).

A second limitation concerns the criteria for patients’ enrollment. In this study, given the presence of an infection, we considered patients to be in overt shock when they remained hypotensive after a fluid challenge with 20 mL/kg of crystalloids. It is interesting to notice that the criteria for the enrollment of patients in studies on septic shock are still not standardized. In published series of septic shock

patients, fluid treatment before enrollment has included anything between 20 mL/kg of Ringer lactate and 30 mL/kg of hydroxyethyl starch. Similarly, the concept of cryptic shock, introduced by Rivers et al [14], to indicate patients who were still normotensive but presented metabolic signs of severe tissue hypoperfusion, is not universally accepted because hyperlactatemia may be due to causes different from tissue hypoperfusion and because it is not yet clear whether and how these patients’ prognosis differ from that of their hypotensive counterparts [44]. For these reasons, available studies in the literature enroll different percentages of septic shock subgroups (ie, “overt” vs “cryptic”) and make any comparison difficult and possibly misleading [45,46].

A third minor limitation was the use in 2 patients (on 25 treated with vasopressors) a high-dose dopamine. This drug was still recommended by SSC at the time of the writing of our first protocol but has been discouraged in the next guidelines after new evidence emerged [47] and we amended the protocol accordingly.

In conclusion, we have shown that the use of serial sonographic evaluation of ?IVC and of B lines in the lung is a feasible way to guide the initial phase of volume replenishment in patients with septic shock. The insertion of a CVC may thus be reserved to patients who do not respond to fluids and need to proceed to treatment with vasopressors. This allows to delay CVC placement to a second phase of treatment, when more clinical evidence is usually available, and physicians may feel more confident with their decision to move on with a procedure, which carries potentially serious side effects.

Although our results suggest the feasibility of a “less invasive” approach to septic shock, a randomized controlled trial will be necessary to prove its noninferiority and its safety compared with the classic EGDT protocol.

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