The ideal heart rate and blood pressure in shock states is a complicated clinical question, as changes in adrenergic output, effective circulating blood volume, and cardiac function can cause varying oxygen deliveries for the same arterial pressure and heart rate. While the body's ability to maintain a compensatory cardiac output in the setting of shock is a primary survival mechanism, there are multiple adverse effects associated with this increased adrenergic output. Maintaining this balance between excessive adrenergic stimulation (increased heart rate and vasomotor tone) and effective homeostasis likely will need to be tailored to the patient's individual physiologic needs, and continues to be refined in clinical trials. Importantly, no ‘one size fits all’ approach will be effective in the general management of patients in circulatory shock. Overall, two recent trials have helped to define the regulation of blood pressure [1▪] and heart rate  in shock state.
Within the context of circulatory shock, normal adaptive sympathetic mechanisms aim to sustain arterial pressure above some minimal value by decreasing unstressed blood volume, usually housed in the systemic venous system, increasing arterial tone to less vital organ systems (e.g. skin and nonexercising muscle). When these adaptive intrinsic systems fail, systemic hypotension develops with an associated decrease in blood flow to vital organ systems. Thus, hypotension is a late phase of shock and reflects failure of these adaptive systems. However, circulatory shock occurs earlier than overt hypotension in most individuals. Importantly, the increased adrenergic tone manifests itself as tachycardia. Thus, tachycardia is a warning signal of intrinsic metabolic stress, whereas hypotension is a medical emergency.
In this study, we review the current peer-reviewed literature related to systemic hypotension and targeted optimal perfusion pressures in shock, as well as the impact of heart rate control on outcome in critical illness.
REGULATION OF BLOOD PRESSURE
Organ perfusion is maintained by a systemic pressure at which autoregulation can occur by local vasodilation. This perfusion pressure varies between patients and specific organ systems , and can be altered by chronic hypertension and sepsis . The target blood pressure in shock is derived from the mean arterial pressure (MAP) needed to maintain this autoregulation. Ischemia from inadequate resuscitation and excessive vasoconstriction may be difficult to distinguish. When arterial pressure needs to be artificially sustained independently of flow, systemic vasopressors are usually administered. Although both dopamine and norepinephrine have traditionally been the most commonly used agents for the support of vasoplegia and systemic hypotension, norepinephrine has emerged as the vasopressor of choice under most conditions due to the lower incidence of arrhythmias and a wider therapeutic dose range . Epinephrine has been used in some older trials, and for acute blood pressure control, phenylephrine and ephedrine are sometimes used. However, in this review, we focus on the use of norepinephrine as the vasopressor to sustain arterial pressure.
Importantly, arterial pressure is not organ perfusion pressure. Organ perfusion pressure varies amongst organs based on tissue type and venous back pressures. Thus, in the management of neurotrauma, calculating cerebral perfusion pressure as MAP minus central venous pressure or intracranial pressure, whichever is higher, is required. For the gut and kidney, intra-abdominal pressure or central venous pressure is the back pressure to blood flow. However, overall, when the goal is to sustain flow to all organs, it is reasonable to target a specific MAP. This review focuses on MAP-targeted global blood flow.
The ideal blood pressure in septic shock varies. Initial analyses associated with patients in septic shock noted that the highest mortality occurred amongst those with a MAP under 65 mmHg  and that a higher target improved neither renal function nor metabolic variables [7,8]. More recent data on larger numbers of patients suggested that higher MAP into the mid-70s targets might be needed to prevent renal dysfunction [9–11]. That said, physiologic studies have demonstrated that septic acute renal failure is associated with a marked increase in blood flow; thus, targeting a specific blood pressure does not guarantee specific organ function [12,13].
Most recently, the Sepsis and Mean Arterial Pressure (SEPSISPAM) trial by Asfar et al. attempted to compare a higher MAP target of 80–85 mmHg with a lower MAP target of 65–70 mmHg. The study demonstrated significantly different MAPs between groups; however, both groups had average MAPs that were higher than their intended targets, essentially creating a comparison between a MAP of 70–80 mmHg and a MAP of 80–90 mmHg. The study failed to show a significant difference in their primary endpoint of 28 and 90-day mortality. The differences in most secondary outcomes were also nonsignificant; however, amongst patients with pre-existing hypertension, the higher MAP target decreased the need for renal replacement therapy, with a number needed to treat of 9.5 to prevent renal replacement therapy in one patient . There was a higher incidence of atrial fibrillation detected in the high MAP target group. The clinical implication of this study is that there is currently no indication for routinely targeting a higher MAP in sepsis. The study provides no new information regarding the traditional minimum MAP of 65 mmHg, since the lower target group had an average MAP of 70–80 mmHg.
On the basis of the data from previous trials as well as SEPSISPAM, an initial MAP target of 65–70 mmHg seems to be reasonable and well tolerated. An individualized approach to blood pressure management is necessary, aiming for a higher MAP of 80–85 mmHg in patients with pre-existing hypertension or based on clinical responses such as urine output, with caution for increased cardiovascular complications as higher doses of inotropes are required . There is also a notable exception for trauma patients in the initial resuscitation period, when there may be benefit to delaying resuscitation until hemostasis can be achieved [16,17]. Once hemostasis is established, a blood pressure target similar to nontrauma patients can be adopted. These data support the current Surviving Sepsis Campaign recommendations for a MAP target of 65 mmHg, with the caveat that pre-existing comorbidities should be considered as to most appropriate MAP target .
Blood pressure regulation should also be accomplished in terms of the timing of vasopressors. A recent retrospective cohort demonstrated a positive association between earlier administration of norepinephrine and improved outcomes in septic shock . Although it is not entirely clear whether this benefit is derived from better care, less fluids, or improved perfusion, this trial does highlight the benefits of the timing of vasopressor administration in addition to solely the target MAP .
The use of intravenous angiotensin II agents for the treatment of distributive shock was shown to have no effect on mortality; however, it is still investigational .
REGULATION OF HEART RATE
The normal response to shock is an increase in adrenergic output as the body attempts to maintain homeostasis. In the case of cardiogenic shock, this tachycardia is necessary to compensate for limits in stroke volume. However, with this caveat, all other forms of shock feature wide variation in heart rate with little change in cardiac output. In these states, the specific impact of hyperadrenergic stimulation on the heart needs to be considered.
High adrenergic output can have multiple adverse physiologic effects, such as hypercoagulability, poor glycemic control, and impaired cardiac function . β-adrenergic blockade has been suggested as a way to protect against the adverse effects of catecholamine toxicity during shock. Interestingly, β-blockade has also been shown to be of benefit in patients with chronic obstructive pulmonary disease and concurrent cardiac disease [23,24]. Although initially feared to precipitously reduce blood pressure and cardiac output, the safety and efficacy of β-blockade has been demonstrated in animal models published over the past 5 years [25,26]. More recent human studies include a pilot study from Morelli et al. of 25 patients in septic shock with tachycardia after 24 h of hemodynamic optimization. The study demonstrated that esmolol infusion was associated with preserved microvascular blood flow and maintenance of stroke volume .
As follow-up to the pilot study, the same group conducted a phase II study on the effect of esmolol titration on tachycardic patients with septic shock on high-dose norepinephrine . Titration of esmolol was not shown to increase adverse outcomes. While intriguing, these results should be interpreted in the setting of two main criticisms. First, all patients required high inotropic support with levosimendan, which is rarely used and expensive, and the use of which has not been fully validated . Additionally, the study population experienced a high overall mortality, which may conceal a potential detrimental impact of β-blockade . Other limitations noted by the authors included the generalizability of the cohort, arbitrary heart rate cut-offs, and the lack of blinding. Despite these limitations, selective β-1 blockade seems to have the potential to protect against the toxicity of excessive adrenergic output while allowing unrestricted α-adrenergic stimulation in a titratable fashion without adversely affecting cardiac output due to excessive afterload. Preserving ventricular function from damage due to the excess adrenergic state may be specifically important, especially given the myocardial dysfunction and cardiomyopathy presumably caused by sepsis itself .
Whether the benefit of heart rate control with β-blockade is primarily due to hemodynamic or immunomodulatory effects remains to be seen . Further study is also needed to define the ideal heart rate and patient population and to examine the effects in patients without tachycardia. Upcoming trials such as Hemodynamic Tolerance and Anti-Inflammatory Effects of Esmolol During the Treatment of Septic Shock (THANE) and Esmolol Effects on Heart Inflammation in Septic Shock (ESMOSEPSIS), designed to investigate these issues, are currently enrolling participants.
At this point, this preliminary phase II trial agrees with older studies showing the safety of β-blockade in other forms of critical illness such as traumatic brain injury and burns [32,33]. Although further trials are needed to better define the ideal heart rate and determine the specific patient population most likely to benefit from β-blockade, at this time, targeting a normal-range heart rate appears safe. Since tachycardia has the potential for many adverse effects, especially in sepsis, and the regulation with β-blockade can be accomplished without cardiovascular collapse in selected, closely monitored patients, heart rate control remains an intriguing endpoint of existing ongoing clinical trials, but not a recommendation for present-day management.
BLOOD PRESSURE AND HEART RATE REGULATION IN CARDIOGENIC SHOCK
The regulation of heart rate and blood pressure in cardiogenic shock remains unchanged, with no new trials published in this patient population. One small series reported on the use of norepinephrine to increase MAP to 85 mmHg for 1 h in 25 patients with cardiogenic shock secondary to myocardial infarction ; however, this study cannot be generalized due to its small size, limited intervention, and lack of variables of cerebral perfusion. The goal of blood pressure regulation in cardiogenic shock remains to afford as much afterload reduction as possible in order to still maintain normal perfusion pressures. If anything, recent trials of aortic balloon counterpulsation and left ventricular assist device use suggest that cardiogenic shock is unique in its mechanical function–flow interactions. However, ongoing clinical trials of mechanical assist devices continue, and we look forward to seeing the result of those studies.
Intensivists are frequently faced with the decision of the ideal blood pressure and heart rate for patients in shock. Although this topic has been frequently examined, the answer is still not definitive. Perhaps, the major takeaway from the last 12 months is that an individualized approach is necessary, tailored to the individual physiological needs of each patient. Few specific conclusions can be made, but the following should be considered. First, in the immediate 6–12 h of septic shock management, targeting a MAP greater than 65 mmHg using vasopressors and fluids as needed is appropriate and without complications, excluding previously hypertensive patients, in whom a targeted MAP of approximately 75–90 mmHg appears reasonable. Second, tachycardia is never a good thing, and pharmacologic blockade of excess adrenergic stimulation in sepsis-induced tachycardia when associated with adequate resuscitative and monitoring efforts appears safe and may be beneficial.
Financial support and sponsorship
The present study was supported in part by NIH Grant HL07820.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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