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Introduction
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With publication of the PROCESS and ARISE trials, many hemodynamic goals are being disproven. There is a growing tide of nihilism. Should we should just give septic patients a couple bags of fluid, some antibiotics, and hope for the best?
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Probably not. PROCESS and ARISE have showed us what we can ignore. Now it's time to focus on hemodynamic targets that do matter. Mean Arterial Pressure (MAP) is easily measured and may provide useful information about the adequacy of perfusion, especially in the first minutes of resuscitation (before measurements such as urine output are available).
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It is common practice to delay initiation of norepinephrine until the patient has received a fair amount of fluid. For patients with mild septic shock, this strategy usually works. However, in severe septic shock fluid administration often fails, so starting with fluid alone delays reaching an adequate MAP. This post explores when to start norepinephrine in a septic patient with an inadequate MAP.
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Physiology: Why target the MAP?
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The MAP is the average pressure driving systemic perfusion. Organs autoregulate their perfusion over a wide range of blood pressure (i.e., vasodilate or vasoconstrict to obtain an adequate perfusion). However, when the MAP falls too low, organs lose the ability to autoregulate and perfusion decreases in a linear fashion with any further decrease in blood pressure:
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One goal of resuscitation is to maintain a MAP above the minimal level required for adequate perfusion (“Target MAP” above). This is typically around 65 mm, although it may be a bit higher in chronic hypertension or a bit lower in younger patients or chronic hypotension. While there is some controversy about exactly what the target MAP should be, it is universally agreed that achieving an adequate MAP is important. However, it is unknown how quickly the target MAP needs to be reached.
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It should be noted that MAP dose not equate with perfusion. For example, increasing the MAP with a pure vasoconstrictor (i.e., phenylephrine) may not improve organ perfusion. However, if MAP is increased without causing excessive vasoconstriction (i.e., with fluid resuscitation and/or norepinephrine), then perfusion will improve. More importantly, if the MAP is clearly inadequate, then the clinician may be fairly certain that perfusion is inadequate(for example, a young person with a MAP of 45mm may look fine but is definitely malperfused).
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Theory behind the traditional fluid-first approach to sepsis
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At some point, most of us were taught that sepsis resuscitation starts with volume resuscitation before starting norepinephrine (“fill the tank”). It is common practice to load septic patients with a certain arbitrary amount of volume (i.e., two liters) before starting norepinephrine. The theory behind this is that septic patients are often intravascularly volume depleted due to third-space losses, so arterial constriction alone could impair perfusion. Another reason to use a fluid-first approach is that this may avoid placing a central line to administer norepinephrine.
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Reasons not to delay norepinephrine in a patient with inadequate MAP
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(1) Septic shock is not only due to hypovolemia
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A fluid-first approach would be valid if septic shock was due to volume depletion. Certainly for a patient with hemorrhagic shock, the first line of treatment is replacement of blood products. However, hypoperfusion in septic shock due to multiple factors(including venodilation, arterial dilation, intravascular volume depletion, and sometimes septic cardiomyopathy). Initiating therapy with fluid alone will only address one of these factors, and therefore often fails.
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(2) Norepinephrine increases preload
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Norepinephrine has numerous effects in sepsis including venoconstriction (increasing preload), arterial constriction, positive inotropy, improved cardiac output, and improved renal perfusion (Marik 2014). This actually represents a balanced approach which addresses all of the physiologic derangements in septic shock. If the patient is intravascularly depleted, norepinephrine may augment preload while volume is being simultaneously infused.
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(3) It's OK to administer peripheral norepinephrine for a short period of time
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One barrier to starting norepinephrine is often lack of a central line. However, it is safe to give norepinephrine peripherally for a limited period of time while stabilizing the patient and placing a central line. This has been covered by Scott Weingart, so please see his site for a discussion of this. The bottom line is that this must be done with care, but can be done safely. If adequate peripheral access cannot be obtained, intraosseous access is another option while awaiting placement of a central line.
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For a patient in whom it is unclear whether norepinephrine will be required for a long period of time, it is reasonable to start peripheral norepinephrine while simultaneously challenging the patient with fluid. If the patient responds to fluid, the norepinephrine may be weaned off rapidly and a central line does not need to be placed.
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(4) Duration of time with inadequate MAP increases risk of renal failure
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The first organ to suffer from hypoperfusion is often the kidney. The risk of renal failure in septic shock relates to hypotension, and may be reduced with the use of norepinephrine to support renal perfusion (Bellomo 2008, Asfar 2014).
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The real question is how urgentlymust the MAP be supported to avoid renal failure? Among a large database of ICU patients, the risk of renal failure related to both the severityof hypotension and also the durationof hypotension (Lehman 2010). At lower blood pressures, the risk of renal failure increased more rapidly over time (figure below). Although this is correlative, it suggests that patients with lower MAP require more urgent stabilization.
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(5) Prolonged hypotension may itself contribute to refractory shock
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Severe shock may propagate itself as patients fall into a death spiral (figure below). This is best recognized in refractory hemorrhagic shock, but may occur in other types of shock as well (Fauci 2008). Hypoperfusion causes tissue damage resulting in the release of inflammatory mediators. The normal response of organs to hypoperfusion is to vasodilate in order to maintain their perfusion (i.e, autoregulation), but when vasodilation occurs in every organ simultaneously it may aggravate the shock state (Angele 2008). It is likely that this death spiral contributes to the physiology of refractory septic shock. Thus, it is possible that prompt hemodynamic stabilization with norepinephrine may prevent patients from slipping into refractory septic shock.
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This phenomenon could contribute to the biphasic relationship of mortality to lowest recorded MAP in a mixed ICU database (figure below; Lehman 2013). Varpula 2005 similarly found a very strong correlation between survival and duration of time spent below MAP<65mm among a cohort of patients with septic shock. Although this is correlative data, it supports the concept that a non-perfusing MAP is undesirable, even for a short time period.
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(6) Not all patients with septic shock are fluid-responsive
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Although most patients with septic shock have some component of intravascular volume depletion, some don't. For example, a patient with underlying cardiomyopathy or cor pulmonale may present with septic shock and intravascular volume overload. Therefore, blindly giving every patient with sepsis an arbitrary amount of crystalloid prior to starting norepinephrine makes little sense. It would be more logical to assess the patient's physiology (e.g. using echocardiography) to determine a tailored resuscitative strategy.
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Clinical evidence
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Four retrospective studies have correlated delay to vasopressor initiation with outcome. Subramanian 2008 found a nonsignificant trend towards increased mortality with early vasopressors. Beck 2014 found a weak correlation between earlier vasopressors and improved mortality. Waechter 2014 found lowest mortality when vasopressors were started 1-6 hours after shock initiation, and recommended avoided vasopressors in the first hour of resuscitation. Bai 2014 found an association between early norepinephrine and survival.
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These studies are all retrospective time-to-intervention studies. As discussed previously, this type of retrospective correlational study is notoriously susceptible to confounding variables. For example, among these studies Beck 2014 and Waechter 2014 were performed by the sameresearch group using the samedatabase of patients, but obtained conflicting results! Furthermore, other than Bai 2014, these studies included at a broad variety of vasopressors with varying mechanisms of action.
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The only quasi-prospective study was Bellomo 2004. These authors developed a sepsis protocol incorporating early use of norepinephrine (indicated if the patient had a MAP<70mm despite fluid resuscitation or a MAP<60mm irrespective of fluid resuscitation). Later they retrospectively studied 142 patients treated in this fashion. There was no control group, but observed mortality was lower than mortality as predicted by SAPS II score (35% vs. 41%, p=0.3). This study supports the safety of early norepinephrine to support MAP, with hints of possible benefit.
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CENSER, a prospective randomized controlled trial of early norepinephrine in septic shock, recently started recruiting patients. Unfortunately the study is projected to run through 2017, so don't hold your breath.
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Many reasonable approaches
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Since there is no high-quality evidence on this topic, there are a wide range of options which are reasonable. The timing of norepinephrine administration should be determined by the bedside clinician on the basis of how severely shocked the patient is, the expected clinical course, and individual hemodynamic assessment. Below is one possible approach.
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- Vital signs are vital. Despite enthusiasm about gadgets, MAP remains useful. A patient with a severely low MAP is probably malperfused, regardless of how well they may appear.
- Patients with septic shock have hypotension due to multiple factors (i.e., venodilation, arterial dilation, reduced preload). Initiating treatment with fluids alone addresses only one factor (reduced preload), explaining why this often fails.
- Norepinephrine increases preload, MAP, and contractility. This is a more rational approach to the multiple hemodynamic derangements in septic shock.
- It makes little sense to delay norepinephrine while awaiting fluid resuscitation in a patient with septic shock and severely low MAP. Delaying hemodynamic stabilization may increase the risk of renal failure and could contribute to worsening shock.
- There is no solid evidence regarding when to start norepinephrine. The decision to initiate norepinephrine should be made on an individualized basis depending on hemodynamic assessment and the judgment of the treating clinician.
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Related Posts on sepsis resuscitation and vasopressors
- Mythbusting: Empty IVC and hyperkinetic heart don't prove volume depletion. This post discusses the physiology of early sepsis, and why norepinephrine may make more sense physiologically compared to volume resuscitation.
- Renoresuscitation: Strategy to avoid chronic sepsis. This post discusses an overall strategy to resuscitation of septic shock focused on avoiding renal injury.
- Renal microvascular hemodynamics in sepsis: a new paradigm. Some thoughts about the physiology of acute kidney injury in septic shock and a possible role for early vasopressin.
Image credits:
– Opening image: http://rtf305-f10-07827-dmi237.blogspot.com/2010/10/neos-journey-matrix-3-act-structure.html
– Death spiral: http://jaypgreene.com/2010/05/13/dc-naep-scores-where-is-the-death-spiral/
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