Hospital Medicine

Considerably fewer patients who develop sepsis are dying of it now, thanks to a number of studies of how to reverse sepsis-induced tissue hypoxia.¹ The greatest strides in improving outcomes have been attributed to better early management, which includes prompt recognition of sepsis, rapid initiation of antimicrobial therapy, elimination of the source of infection, and early goal-directed therapy. Thus, even though the incidence of severe sepsis and septic shock is increasing,^2,3 the Surviving Sepsis Campaign has documented a significant decrease in unadjusted mortality rates (37% to 30.8%) associated with the bundled approach in the management of sepsis.⁴ (We will talk about this later in the article.)

This review will summarize the evidence for the early management of septic shock and will evaluate the various treatment decisions beyond the initial phases of resuscitation.

INFLAMMATION AND VASODILATION

Sepsis syndrome starts with an infection that leads to a proinflammatory state with a complex interaction between anti-inflammatory and proinflammatory mediators, enhanced coagulation, and impaired fibrinolysis.^5,6

Sepsis induces vasodilation by way of inappropriate activation of vasodilatory mechanisms (increased synthesis of nitric oxide and vasopressin deficiency) and failure of vasoconstrictor mechanisms (activation of ATP-sensitive potassium channels in vascular smooth muscle).⁷ Thus, the hemodynamic abnormalities are multifactorial, and the resultant tissue hypoperfusion further contributes to the proinflammatory and procoagulant state, precipitating multiorgan dysfunction and, often, death.

DEFINITIONS

• Sepsis—infection together with systemic manifestation of inflammatory response
• Severe sepsis—sepsis plus induced organ dysfunction or evidence of tissue hypoperfusion
• Septic shock—sepsis-induced hypotension persisting despite adequate fluid resuscitation.

EARLY MANAGEMENT OF SEPTIC SHOCK

Early in the course of septic shock, the physician’s job is to:

• Recognize it promptly
• Begin empiric antibiotic therapy quickly
• Eliminate the source of infection, if applicable, eg, by removing an infected central venous catheter
• Give fluid resuscitation, titrated to specific goals
• Give vasopressor therapy to maintain blood pressure, organ perfusion, and oxygen delivery (Table 1).

The line between “early” and “late” is not clear. Traditionally, it has been drawn at 6 hours from presentation, and this cutoff was used in some of the studies we will discuss here.

Recognizing severe sepsis early in its course

The diagnosis of severe sepsis may be challenging, since up to 40% of patients may present with cryptic shock. These patients may not be hemodynamically compromised but may show evidence of tissue hypoxia, eg, an elevated serum lactate concentration or a low central venous oxygen saturation (Scvo₂), or both.⁸ In view of this, much effort has gone into finding a biomarker that, in addition to clinical features, can help identify patients in an early stage of sepsis.

Procalcitonin levels rise in response to severe bacterial infection,⁹ and they correlate with sepsis-related organ failure scores and outcomes.^10,11 Thus, the serum procalcitonin level may help in assessing the severity of sepsis, especially when combined with standard clinical and laboratory variables. However, controversy exists about the threshold to use in making decisions about antibiotic therapy and the value of this test in differentiating severe noninfectious inflammatory reactions from infectious causes of shock.¹² Therefore, it is not widely used in clinical practice.

Serum lactate has been used for decades as a marker of tissue hypoperfusion. It is typically elevated in patients with severe sepsis and septic shock, and although the hyperlactatemia could be a result of global hypoperfusion, it can also be secondary to sepsis-induced mitochondrial dysfunction,¹³ impaired pyruvate dehydrogenase activity,¹⁴ increased aerobic glycolysis by catecholamine-stimulated sodium-potassium pump hyperactivity,¹⁵ and even impaired clearance.¹⁶

But whatever the mechanism, elevated lactate in severe sepsis and septic shock predicts a poor outcome and may help guide aggressive resuscitation. In fact, early lactate clearance (ie, normalization of an elevated value on repeat testing within the first 6 hours) is associated with better outcomes in patients with severe sepsis and septic shock.^17,18

Panels of biomarkers. A literature search revealed over 3,000 papers on 178 different biomarkers in sepsis.¹⁹ Many of these biomarkers lack sufficient specificity and sensitivity for clinical use, and thus some investigators have suggested using a panel of them to enhance their predictive ability. Shapiro et al²⁰ evaluated 971 patients admitted to the emergency department with suspected infection and discovered that a panel of three biomarkers (neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist) was highly predictive of severe sepsis, septic shock, and death.

As soon as severe sepsis and septic shock are recognized, it is imperative that adequate empiric antibiotic treatment be started, along with infectious source control if applicable.²¹ The Surviving Sepsis Campaign guidelines recommend starting intravenous antibiotics as early as possible—within the first hour of recognition of severe sepsis with or without septic shock.²²

Kumar et al,²³ in a multicenter retrospective study of patients with septic shock, found that each hour of delay in giving appropriate antimicrobial agents in the first 6 hours from the onset of hypotension was associated with a 7.6% decrease in the in-hospital survival rate.

In a similar study,²⁴ the same investigators analyzed data from 5,715 septic shock patients regarding the impact of starting the right antimicrobial therapy. Appropriate antimicrobial agents (ie, those having in vitro activity against the isolated pathogens) were given in 80.1% of cases, and the survival rate in those who received appropriate antibiotics was drastically higher than in those who received inappropriate ones (52.0% vs 10.3%, P < .0001).

In addition, two recent studies evaluated the importance of early empiric antibiotic therapy in conjunction with resuscitative protocols.^25,26 In a preplanned analysis of early antimicrobial use in a study comparing lactate clearance and Scvo₂ as goals of therapy, Puskarich et al²⁶ found that fewer patients who received antibiotics before shock was recognized (according to formal criteria) died. Similarly, in a retrospective study in patients presenting to the emergency department and treated with early goal-directed therapy (defined below), Gaieski et al²⁵ found that the mortality rate was drastically lower when antibiotics were started within 1 hour of either triage or initiation of early goal-directed therapy.

In short, it is imperative to promptly start the most appropriate broad-spectrum antibiotics to target the most likely pathogens based on site of infection, patient risk of multidrug-resistant pathogens, and local susceptibility patterns.

Goal-directed resuscitative therapy

As with antimicrobial therapy, resuscitative therapy should be started early and directed at defined goals.

Rivers et al²⁷ conducted a randomized, controlled study in patients with severe sepsis or septic shock presenting to an emergency department of an urban teaching hospital. The patients were at high risk and had either persistent hypotension after a fluid challenge or serum lactate levels of 4 mmol/L or higher.

Two hundred sixty patients were randomized to receive either early goal-directed therapy in a protocol aimed at maximizing the intravascular volume and correcting global tissue hypoxia or standard therapy in the first 6 hours after presentation. The goals in the goal-directed therapy group were:

• Central venous pressure 8 to 12 mm Hg (achieved with aggressive fluid resuscitation with crystalloids)
• Mean arterial blood pressure greater than 65 mm Hg (maintained with vasoactive drugs, if necessary)
• Scvo₂ above 70%. To achieve this third goal, packed red blood cells were infused to reach a target hematocrit of greater than 30%. For patients with a hematocrit higher than 30% but still with an Scvo₂ less than 70%, inotropic agents were added and titrated to the Scvo₂ goal of 70%.

Goal-directed therapy reduced the in-hospital mortality rate by 16% (the mortality rates were 30.5% in the goal-directed group and 46.5% in the standard therapy group, P = .009) and also reduced the 28- and 60-day mortality rates by similar proportions.²⁷

Subsequent studies of a protocol for early recognition and treatment of sepsis have concluded that early aggressive fluid resuscitation decreases the ensuing need for vasopressor support.²⁸ A resuscitation strategy based on early goal-directed therapy is a major component of the initial resuscitation bundle recommended by the Surviving Sepsis Campaign.²² (A “bundle” refers to the implementation of a core set of recommendations involving the simultaneous adaptation of a number of interventions.)

Areas of debate. However, concerns have been raised about the design of the study by Rivers et al and the mortality rate in the control group, which was higher than one would expect from the patients’ Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.²⁹ In particular, the bundled approach they used precludes the ability to differentiate which interventions were responsible for the outcome benefits. Indeed, there were two major interventions in the early goal-directed therapy group: a protocol for achieving the goals described and the use of Scvo₂ as a goal.

Aggressive fluid resuscitation is considered the most critical aspect of all the major interventions, and there is little argument on its value. The debate centers on central venous pressure as a preload marker, since after the publication of the early goal-directed therapy trial,²⁷ several studies showed that central venous pressure may not be a valid measure to predict fluid responsiveness (discussed later in this paper).^30,31

The choice of colloids or crystalloids for fluid resuscitation is another area of debate. Clinical evidence suggests that albumin is equivalent to normal saline in a heterogeneous intensive care unit population,³² but subgroup analyses suggest albumin may be superior in patients with septic shock.³³ Studies are ongoing (NCT00707122, NCT01337934, and NCT00318942). The use of hydroxyethyl starch in severe sepsis is associated with higher rates of acute renal failure and need for renal replacement therapy than Ringer’s lactate,³⁴ and is generally not recommended. This is further substantiated by two recent randomized controlled studies, which found that the use of hydroxyethyl starch for fluid resuscitation in severe sepsis, compared with crystalloids, did not reduce the mortality rate (and even increased it in one study), and was associated with more need for renal replacement therapy.^35,36

The use of Scvo₂ is yet another topic of debate, and other monitoring variables have been evaluated. A recent study assessed the noninferiority of incorporating venous lactate clearance into the early goal-directed therapy protocol vs Scvo₂.³⁷ Both groups had identical goals for central venous pressure and mean arterial pressure but differed in the use of lactate clearance (defined as at least a 10% decline) or Scvo₂ (> 70%) as the goal for improving tissue hypoxia. There were no significant differences between groups in their in-hospital mortality rates (17% in the lactate clearance group vs 23% in the Scvo₂ group; criteria for noninferiority met). This suggests that lactate may be an alternative to Scvo₂ as a goal in early goal-directed therapy. However, a secondary analysis of the data revealed a lack of concordance in achieving lactate clearance and Scvo₂ goals, which suggests that these parameters may be measuring distinct physiologic processes.³⁸ Since the hemodynamic profiles of septic shock patients are complex, it may be prudent to use both of these markers of resuscitation until further studies are completed.

Given the debate, a number of prospective randomized trials are under way to evaluate resuscitative interventions. These include the Protocolized Care for Early Septic Shock trial (NCT00510835), the Australasian Resuscitation in Sepsis Evaluation trial (NCT00975793), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (ISRCTN 36307479). These three trials will evaluate, collectively, close to 4,000 patients and will provide considerable insights into resuscitative interventions in septic shock.

If fluid therapy does not restore perfusion, vasopressors should be promptly initiated, as the longer that hypotension goes on, the lower the survival rate.³⁹

But which vasopressor should be used? The early goal-directed therapy protocol used in the study by Rivers et al²⁷ did not specify which vasopressor should be used to keep the mean arterial pressure above 65 mm Hg.

The Surviving Sepsis Campaign²² recommends norepinephrine as the first-choice vasopressor, with dopamine as an alternative only in selected patients, such as those with absolute or relative bradycardia.

The guidelines also recommend epinephrine to be added to or substituted for norepinephrine when an additional catecholamine is needed to maintain adequate blood pressure.²² Furthermore, vasopressin at a dose of 0.03 units/min can be added to norepinephrine with the intent of raising the blood pressure or decreasing the norepinephrine requirement. Higher doses of vasopressin should be reserved for salvage therapy.

Regarding phenylephrine, the guidelines recommend against its use except when norepinephrine use is associated with significant tachyarrhythmias, cardiac output is known to be higher, or as a salvage therapy.²²

This is a topic of debate, with recent clinical studies offering further insight.

De Backer et al⁴⁰ compared the effects of dopamine vs norepinephrine for the treatment of shock in 1,679 patients, 62% of whom had septic shock. Overall, there was a trend towards better outcomes with norepinephrine, but no significant difference in mortality rates at 28 days (52.5% with dopamine vs 48.5% with norepinephrine, P = .10). Importantly, fewer patients who were randomized to norepinephrine developed arrhythmias (12.4% vs 24.1%, P < .001), and the norepinephrine group required fewer days of study drug (11.0 vs 12.5, P = .01) and open-label vasopressors (12.6 vs 14.2, P = .007). Of note, patients with cardiogenic shock randomized to norepinephrine had a significantly lower mortality rate than those randomized to dopamine. Although no significant difference in outcome was found between the two vasopressors in the subgroup of patients with septic shock, the overall improvements in secondary surrogate markers suggest that norepinephrine should be the first-line agent.

Norepinephrine has also been compared with “secondary” vasopressors. Annane et al,⁴¹ in a prospective multicenter randomized controlled study, evaluated the effect of norepinephrine plus dobutamine vs epinephrine alone in managing septic shock. There was no significant difference in the primary outcome measure of 28-day mortality (34% with norepinephrine plus dobutamine vs 40% with epinephrine alone, P = .31). However, the study was powered to evaluate for an absolute risk reduction of 20% in the mortality rate, which would be a big reduction. A smaller reduction in the mortality rate, which would not have been statistically significant in this study, might still be considered clinically significant. Furthermore, the group randomized to norepinephrine plus dobutamine had more vasopressor-free days (20 days vs 22 days, P = .05) and less acidosis on days 1 to 4 than the group randomized to epinephrine.

Norepinephrine was also compared with phenylephrine as a first-line vasopressor in a randomized controlled trial in 32 patients with septic shock. No difference was found in cardiopulmonary performance, global oxygen transport, or regional hemodynamics between phenylephrine and norepinephrine.⁴²

While encouraging, these preliminary data need to be verified in a larger randomized controlled trial with concrete outcome measures before being clinically adapted. Taken together, the above studies suggest that norepinephrine should be the initial vasopressor of choice for patients with septic shock.

CONTINUED MANAGEMENT OF SEPTIC SHOCK

How to manage septic shock after the initial stages is much less defined.

Uncertainty persists about the importance of achieving the early goals of resuscitation in patients who did not reach them in the initial 6 hours of treatment. Although there are data suggesting that extending the goals beyond the initial 6 hours may be beneficial, clinicians should use caution when interpreting these results in light of the observational design of the studies.^43,44 For the purpose of this discussion, “continued management” of septic shock will mean after the first 6 hours and after all the early goals are met.

The clinical decisions necessary after the initial stages of resuscitation include:

• Whether further fluid resuscitation is needed
• Assessment for further and additional hemodynamic therapies
• Consideration of adjunctive therapies
• Reevaluation of antibiotic choices (Table 2).

Is more fluid needed? How can we tell?

There is considerable debate about the ideal method for assessing fluid responsiveness. In fact, one of the criticisms of the early goal-directed therapy study²⁷ was that it used central venous pressure as a marker of fluid responsiveness.

Several studies have shown that central venous pressure or pulmonary artery occlusion pressure may not be valid measures of fluid responsiveness.⁴⁵ In fact, in a retrospective study of 150 volume challenges, the area under the receiver-operating-characteristics curve of central venous pressure as a marker of fluid responsiveness was only 0.58. (Recall that the closer the area under the curve is to 1.0, the better the test; a value of 0.50 is the same as chance.) The area under the curve for pulmonary artery occlusion pressure was 0.63.⁴⁶

In contrast, several dynamic indices have been proposed to better guide fluid resuscitation in mechanically ventilated patients.³¹ These are based on changes in stroke volume, aortic blood flow, or arterial pulse pressure in response to the ventilator cycle or passive leg-raising. A detailed review of these markers can be found elsewhere,³¹ but taken together, they have a sensitivity and specificity of over 90% for predicting fluid responsiveness. Clinicians may consider using dynamic markers of fluid responsiveness to determine when to give additional fluids, particularly after the first 6 hours of shock, in which data supporting the use of central venous pressure are lacking.

Optimal use of fluids is particularly important, since some studies suggest that “overresuscitation” has negative consequences. In a multicenter observational study of 1,177 patients with sepsis, after adjusting for a number of comorbidities and baseline severity of illness, the cumulative fluid balance in the first 72 hours after the onset of sepsis was independently associated with a worse mortality rate.⁴⁷

Furthermore, in a retrospective analysis of a randomized controlled trial of vasopressin in conjunction with norepinephrine for septic shock, patients in the highest quartile of fluid balance (more fluid in than out) at 12 hours and 4 days after presentation had significantly higher mortality rates than those in the lowest two quartiles.⁴⁸ The worse outcome with a positive fluid balance might be explained by worsening oxygenation and prolonged mechanical ventilation, as demonstrated by the Fluid and Catheter Treatment Trial in patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS).⁴⁹ Indeed, when fluid balance in patients with septic shockinduced ALI/ARDS was evaluated, patients with both adequate initial fluid resuscitation and conservative late fluid management had a lower mortality rate than those with either one alone.⁵⁰

In view of these findings, especially beyond the initial hours of resuscitation, clinicians should remember that further unnecessary fluid administration may have detrimental effects. Therefore, given the superior predictive abilities of dynamic markers of fluid responsiveness, these should be used to determine the need for further fluid boluses.

In cases in which patients are no longer fluid-responsive and need increasing levels of hemodynamic support, clinicians still have a number of options. These include increasing the current vasopressor dose or starting an additional therapy such as an alternative catecholamine vasopressor, vasopressin, inotropic therapy, or an adjunctive therapy such as a corticosteroid. The intervention could also be a combination of the above choices.

The optimal time point or vasopressor dose at which to consider initiating additional therapies is unknown. However, the Vasopressin and Septic Shock Trial (VASST) provides some insight.⁵¹

This study compared two strategies: escalating doses of norepinephrine vs adding vasopressin to norepinephrine. Overall, adding vasopressin showed no benefit in terms of a lower mortality rate. However, in the subgroup of patients with norepinephrine requirements of 5 to 14 μg/min at study enrollment (ie, a low dose, reflecting less-severe sepsis) vasopressin was associated with a lower 28-day mortality rate (26.5% vs 35.7%, P = .05) and 90-day mortality rate (35.8% vs 46.1%, P = .04). Benefit was also noted in patients with other markers of lower disease severity such as low lactate levels or having received a single vasopressor at baseline.⁵¹

Although subgroup analyses should not generally be used to guide treatment decisions, a prospective trial may never be done to evaluate adding vasopressin to catecholamines earlier vs later. Thus, clinicians who choose to use vasopressin may consider starting this therapy when catecholamine doses are relatively low or before profound hyperlactatemia from prolonged tissue hypoxia has developed.

There is less evidence to guide clinicians who are considering adding a different catecholamine. The theoretical concerns of splanchnic ischemia and cardiac arrhythmia associated with higher doses of catecholamines are usually the impetus to limit a single catecholamine to a “maximum” dose. However, studies that have evaluated combination catecholamine therapies have generally studied combinations of vasopressors with inotropes and lacked standardization in their protocols, thus making them difficult to interpret.^52–54 One could also argue that additional catecholamine therapies, which all function similarly, may have additive effects and cause even more adverse effects. As such, adding another vasopressor should be reserved for patients experiencing noticeable adverse effects (such as tachycardia) on first-line therapy.

Inotropic support

Left ventricular function should be assessed in all patients who continue to be hypotensive despite adequate fluid resuscitation and vasopressor therapy. In a study of patients with septic shock in whom echocardiography was performed daily for the first 3 days of hemodynamic support, new-onset left ventricular hypokinesia was found in 26 (39%) of 67 patients on presentation and in an additional 14 patients (21%) after at least 24 hours of norepinephrine.⁵⁵ Adding inotropic support with dobutamine or epinephrine led to decreases in vasopressor dose and enhanced left ventricular ejection fraction.

In short, left ventricular hypokinesia is common in septic shock, may occur at presentation or after a period of vasopressor support, and is usually correctable with the addition of inotropic support.

Corticosteroids

Beyond hemodynamic support with fluids and catecholamines or vasopressin (or both), clinicians should also consider adjunctive corticosteroid therapy. However, for many years the issue has been controversial for patients with severe sepsis and septic shock.

Annane et al⁵⁶ conducted a large, multicenter, randomized, double-blind, placebocontrolled trial to assess the effect of low doses of corticosteroids in patients with refractory septic shock. Overall, the 28-day mortality rate was 61% in the treatment group and 55% in the placebo group, which was not statistically significant (adjusted odds ratio 0.65, 95% confidence interval 0.39–1.07, P value .09). However, when separated by response to cosyntropin stimulation, those with a change in cortisol of 9 ug/dL or less (nonresponders) randomized to receive corticosteroids had significantly higher survival rates in the short term (28 days) and the long term (1 year). The positive results of this study led to the adoption of low-dose hydrocortisone as standard practice in most patients with septic shock.⁵⁷

But then, to evaluate the effects of corticosteroids in a broader intensive-care population with septic shock, another trial was designed: the Corticosteroid Therapy of Septic Shock (CORTICUS) trial.⁵⁸ Surprisingly, this multicenter, randomized, double-blind, placebo-controlled trial found no significant difference in survival between the group that received hydrocortisone and the placebo group, regardless of response to a cosyntropin stimulation test.

Taking into account the above studies and other randomized controlled trials, the 2012 Surviving Sepsis Campaign guidelines and the International Task Force for the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients recommend intravenous hydrocortisone therapy in adults with septic shock whose blood pressure responds poorly to fluid resuscitation and vasopressor therapy. These consensus statements do not recommend the cosyntropin stimulation test to identify patients with septic shock who should receive corticosteroids.^22,59 The guidelines, however, do not explicitly define poor response to initial therapy.

Of note, in the Annane study, which found a lower mortality rate with corticosteroids, the patients were severely ill, with a mean baseline norepinephrine dose of 1.1 μg/kg/min. In contrast, in the CORTICUS study (which found no benefit of hydrocortisone), patients had lower baseline vasopressor doses, with a mean norepinephrine dose of 0.5 μg/kg/min.

While corticosteroids are associated with a higher rate of shock reversal 7 days after initiation, ⁵⁹ this has not translated into a consistent reduction in the death rate. If a clinician is considering adding corticosteroids to decrease the risk of death, it would seem prudent to add this therapy in patients receiving norepinephrine in doses above 0.5 μg/kg/min.

The ideal sequence and combination of the above therapies including fluids, catecholamine vasopressors, vasopressin, inotropes, and vasopressors have not been elucidated. However, some preliminary evidence suggests an advantage with the combination of vasopressin and corticosteroids. In a subgroup analysis of the VASST study, in patients who received corticosteroids, the combination of vasopressin plus norepinephrine was associated with a lower 28-day mortality rate than with norepinephrine alone (35.9% vs 44.7%, P = .03).⁶⁰ These findings have been replicated in other studies,^61,62 prompting suggestions for a study of vasopressin with and without corticosteroids in patients on norepinephrine to elucidate the role of each therapy individually and in combination.

Tight glycemic control

As with corticosteroids, the pendulum for tight glycemic control in critically ill patients has swung widely in recent years. Enthusiasm was high at first after the publication of a study by van den Berghe et al, which described a 3.4% absolute reduction in mortality with intensive insulin therapy to maintain blood glucose at or below 110 mg/dL.⁶³ However, the significant benefits found in this study were never replicated.

In fact, recent evidence suggests that tight glycemic control is associated with no benefit and a higher risk of hypoglycemia.^34,64 In the largest randomized controlled trial of this topic, with more than 6,000 patients, intensive insulin therapy with a target blood glucose level of 81 to 108 mg/dL was associated with a significantly higher mortality rate (odds ratio 1.14, 95% confidence interval 1.02–1.28, P = .02) than with a target glucose level of less than 180 mg/dL.⁶⁵ Furthermore, in a recent follow-up analysis,⁶⁶ moderate hypoglycemia (serum glucose 41–70 mg/dL) and severe hypoglycemia (serum glucose < 41 mg/dL) were associated with a higher rate of death in a dose-response relationship.⁶⁶

Taking this information together, clinicians should be aware that there is no additional benefit in lowering blood glucose below the range of 140 to 180 mg/dL, and that doing so may be harmful.

Drotecogin alfa

Drotecogin alfa (Xigris) was another adjunctive therapy that has fallen from favor. It was approved for the treatment of severe sepsis in light of promising findings in initial studies.⁶⁷

However, on October 25, 2011, drotecogin alfa was voluntarily withdrawn from the market by the manufacturer after another study found no beneficial effect on the mortality rates at 28 days or at 90 days.⁶⁸ Furthermore, no difference could be found regarding any predetermined primary or secondary outcome measures.

Continued antibiotic therapy

The decision whether to continue initial empiric antimicrobial coverage, broaden it, or de-escalate must be faced for all patients with septic shock, and is ultimately clinical.

The serum procalcitonin level has been proposed to guide antibiotic discontinuation in several clinical settings, although there are still questions about the safety of such an approach. The largest randomized trial published to date reported that a procalcitoninguided strategy to treat suspected bacterial infections in nonsurgical patients could reduce antibiotic exposure with no apparent adverse outcomes.⁶⁹ On the other hand, other data discourage the use of procalcitonin-guided antimicrobial escalation, as this approach did not improve survival and worsened organ function and length of stay in the intensive care unit.⁷⁰

The Surviving Sepsis Campaign guidelines recommend combination antibiotic therapy for no longer than 3 to 5 days and limiting the duration of antibiotics in most cases to 7 to 10 days.²²

TRIALS ARE ONGOING

The understanding of the pathophysiology and treatment of sepsis has greatly advanced over the last decade. Adoption of evidence-based protocols for managing patients with septic shock has improved outcomes. Nevertheless, many multicenter trials are being conducted worldwide to look into some of the most controversial therapies, and their results will guide therapy in the future.

Considerably fewer patients who develop sepsis are dying of it now, thanks to a number of studies of how to reverse sepsis-induced tissue hypoxia.¹ The greatest strides in improving outcomes have been attributed to better early management, which includes prompt recognition of sepsis, rapid initiation of antimicrobial therapy, elimination of the source of infection, and early goal-directed therapy. Thus, even though the incidence of severe sepsis and septic shock is increasing,^2,3 the Surviving Sepsis Campaign has documented a significant decrease in unadjusted mortality rates (37% to 30.8%) associated with the bundled approach in the management of sepsis.⁴ (We will talk about this later in the article.)

This review will summarize the evidence for the early management of septic shock and will evaluate the various treatment decisions beyond the initial phases of resuscitation.

INFLAMMATION AND VASODILATION

Sepsis syndrome starts with an infection that leads to a proinflammatory state with a complex interaction between anti-inflammatory and proinflammatory mediators, enhanced coagulation, and impaired fibrinolysis.^5,6

Sepsis induces vasodilation by way of inappropriate activation of vasodilatory mechanisms (increased synthesis of nitric oxide and vasopressin deficiency) and failure of vasoconstrictor mechanisms (activation of ATP-sensitive potassium channels in vascular smooth muscle).⁷ Thus, the hemodynamic abnormalities are multifactorial, and the resultant tissue hypoperfusion further contributes to the proinflammatory and procoagulant state, precipitating multiorgan dysfunction and, often, death.

DEFINITIONS

• Sepsis—infection together with systemic manifestation of inflammatory response
• Severe sepsis—sepsis plus induced organ dysfunction or evidence of tissue hypoperfusion
• Septic shock—sepsis-induced hypotension persisting despite adequate fluid resuscitation.

EARLY MANAGEMENT OF SEPTIC SHOCK

Early in the course of septic shock, the physician’s job is to:

• Recognize it promptly
• Begin empiric antibiotic therapy quickly
• Eliminate the source of infection, if applicable, eg, by removing an infected central venous catheter
• Give fluid resuscitation, titrated to specific goals
• Give vasopressor therapy to maintain blood pressure, organ perfusion, and oxygen delivery (Table 1).

The line between “early” and “late” is not clear. Traditionally, it has been drawn at 6 hours from presentation, and this cutoff was used in some of the studies we will discuss here.

Recognizing severe sepsis early in its course

The diagnosis of severe sepsis may be challenging, since up to 40% of patients may present with cryptic shock. These patients may not be hemodynamically compromised but may show evidence of tissue hypoxia, eg, an elevated serum lactate concentration or a low central venous oxygen saturation (Scvo₂), or both.⁸ In view of this, much effort has gone into finding a biomarker that, in addition to clinical features, can help identify patients in an early stage of sepsis.

Procalcitonin levels rise in response to severe bacterial infection,⁹ and they correlate with sepsis-related organ failure scores and outcomes.^10,11 Thus, the serum procalcitonin level may help in assessing the severity of sepsis, especially when combined with standard clinical and laboratory variables. However, controversy exists about the threshold to use in making decisions about antibiotic therapy and the value of this test in differentiating severe noninfectious inflammatory reactions from infectious causes of shock.¹² Therefore, it is not widely used in clinical practice.

Serum lactate has been used for decades as a marker of tissue hypoperfusion. It is typically elevated in patients with severe sepsis and septic shock, and although the hyperlactatemia could be a result of global hypoperfusion, it can also be secondary to sepsis-induced mitochondrial dysfunction,¹³ impaired pyruvate dehydrogenase activity,¹⁴ increased aerobic glycolysis by catecholamine-stimulated sodium-potassium pump hyperactivity,¹⁵ and even impaired clearance.¹⁶

But whatever the mechanism, elevated lactate in severe sepsis and septic shock predicts a poor outcome and may help guide aggressive resuscitation. In fact, early lactate clearance (ie, normalization of an elevated value on repeat testing within the first 6 hours) is associated with better outcomes in patients with severe sepsis and septic shock.^17,18

Panels of biomarkers. A literature search revealed over 3,000 papers on 178 different biomarkers in sepsis.¹⁹ Many of these biomarkers lack sufficient specificity and sensitivity for clinical use, and thus some investigators have suggested using a panel of them to enhance their predictive ability. Shapiro et al²⁰ evaluated 971 patients admitted to the emergency department with suspected infection and discovered that a panel of three biomarkers (neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist) was highly predictive of severe sepsis, septic shock, and death.

As soon as severe sepsis and septic shock are recognized, it is imperative that adequate empiric antibiotic treatment be started, along with infectious source control if applicable.²¹ The Surviving Sepsis Campaign guidelines recommend starting intravenous antibiotics as early as possible—within the first hour of recognition of severe sepsis with or without septic shock.²²

Kumar et al,²³ in a multicenter retrospective study of patients with septic shock, found that each hour of delay in giving appropriate antimicrobial agents in the first 6 hours from the onset of hypotension was associated with a 7.6% decrease in the in-hospital survival rate.

In a similar study,²⁴ the same investigators analyzed data from 5,715 septic shock patients regarding the impact of starting the right antimicrobial therapy. Appropriate antimicrobial agents (ie, those having in vitro activity against the isolated pathogens) were given in 80.1% of cases, and the survival rate in those who received appropriate antibiotics was drastically higher than in those who received inappropriate ones (52.0% vs 10.3%, P < .0001).

In addition, two recent studies evaluated the importance of early empiric antibiotic therapy in conjunction with resuscitative protocols.^25,26 In a preplanned analysis of early antimicrobial use in a study comparing lactate clearance and Scvo₂ as goals of therapy, Puskarich et al²⁶ found that fewer patients who received antibiotics before shock was recognized (according to formal criteria) died. Similarly, in a retrospective study in patients presenting to the emergency department and treated with early goal-directed therapy (defined below), Gaieski et al²⁵ found that the mortality rate was drastically lower when antibiotics were started within 1 hour of either triage or initiation of early goal-directed therapy.

In short, it is imperative to promptly start the most appropriate broad-spectrum antibiotics to target the most likely pathogens based on site of infection, patient risk of multidrug-resistant pathogens, and local susceptibility patterns.

Goal-directed resuscitative therapy

As with antimicrobial therapy, resuscitative therapy should be started early and directed at defined goals.

Rivers et al²⁷ conducted a randomized, controlled study in patients with severe sepsis or septic shock presenting to an emergency department of an urban teaching hospital. The patients were at high risk and had either persistent hypotension after a fluid challenge or serum lactate levels of 4 mmol/L or higher.

Two hundred sixty patients were randomized to receive either early goal-directed therapy in a protocol aimed at maximizing the intravascular volume and correcting global tissue hypoxia or standard therapy in the first 6 hours after presentation. The goals in the goal-directed therapy group were:

• Central venous pressure 8 to 12 mm Hg (achieved with aggressive fluid resuscitation with crystalloids)
• Mean arterial blood pressure greater than 65 mm Hg (maintained with vasoactive drugs, if necessary)
• Scvo₂ above 70%. To achieve this third goal, packed red blood cells were infused to reach a target hematocrit of greater than 30%. For patients with a hematocrit higher than 30% but still with an Scvo₂ less than 70%, inotropic agents were added and titrated to the Scvo₂ goal of 70%.

Goal-directed therapy reduced the in-hospital mortality rate by 16% (the mortality rates were 30.5% in the goal-directed group and 46.5% in the standard therapy group, P = .009) and also reduced the 28- and 60-day mortality rates by similar proportions.²⁷

Subsequent studies of a protocol for early recognition and treatment of sepsis have concluded that early aggressive fluid resuscitation decreases the ensuing need for vasopressor support.²⁸ A resuscitation strategy based on early goal-directed therapy is a major component of the initial resuscitation bundle recommended by the Surviving Sepsis Campaign.²² (A “bundle” refers to the implementation of a core set of recommendations involving the simultaneous adaptation of a number of interventions.)

Areas of debate. However, concerns have been raised about the design of the study by Rivers et al and the mortality rate in the control group, which was higher than one would expect from the patients’ Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.²⁹ In particular, the bundled approach they used precludes the ability to differentiate which interventions were responsible for the outcome benefits. Indeed, there were two major interventions in the early goal-directed therapy group: a protocol for achieving the goals described and the use of Scvo₂ as a goal.

Aggressive fluid resuscitation is considered the most critical aspect of all the major interventions, and there is little argument on its value. The debate centers on central venous pressure as a preload marker, since after the publication of the early goal-directed therapy trial,²⁷ several studies showed that central venous pressure may not be a valid measure to predict fluid responsiveness (discussed later in this paper).^30,31

The choice of colloids or crystalloids for fluid resuscitation is another area of debate. Clinical evidence suggests that albumin is equivalent to normal saline in a heterogeneous intensive care unit population,³² but subgroup analyses suggest albumin may be superior in patients with septic shock.³³ Studies are ongoing (NCT00707122, NCT01337934, and NCT00318942). The use of hydroxyethyl starch in severe sepsis is associated with higher rates of acute renal failure and need for renal replacement therapy than Ringer’s lactate,³⁴ and is generally not recommended. This is further substantiated by two recent randomized controlled studies, which found that the use of hydroxyethyl starch for fluid resuscitation in severe sepsis, compared with crystalloids, did not reduce the mortality rate (and even increased it in one study), and was associated with more need for renal replacement therapy.^35,36

The use of Scvo₂ is yet another topic of debate, and other monitoring variables have been evaluated. A recent study assessed the noninferiority of incorporating venous lactate clearance into the early goal-directed therapy protocol vs Scvo₂.³⁷ Both groups had identical goals for central venous pressure and mean arterial pressure but differed in the use of lactate clearance (defined as at least a 10% decline) or Scvo₂ (> 70%) as the goal for improving tissue hypoxia. There were no significant differences between groups in their in-hospital mortality rates (17% in the lactate clearance group vs 23% in the Scvo₂ group; criteria for noninferiority met). This suggests that lactate may be an alternative to Scvo₂ as a goal in early goal-directed therapy. However, a secondary analysis of the data revealed a lack of concordance in achieving lactate clearance and Scvo₂ goals, which suggests that these parameters may be measuring distinct physiologic processes.³⁸ Since the hemodynamic profiles of septic shock patients are complex, it may be prudent to use both of these markers of resuscitation until further studies are completed.

Given the debate, a number of prospective randomized trials are under way to evaluate resuscitative interventions. These include the Protocolized Care for Early Septic Shock trial (NCT00510835), the Australasian Resuscitation in Sepsis Evaluation trial (NCT00975793), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (ISRCTN 36307479). These three trials will evaluate, collectively, close to 4,000 patients and will provide considerable insights into resuscitative interventions in septic shock.

If fluid therapy does not restore perfusion, vasopressors should be promptly initiated, as the longer that hypotension goes on, the lower the survival rate.³⁹

But which vasopressor should be used? The early goal-directed therapy protocol used in the study by Rivers et al²⁷ did not specify which vasopressor should be used to keep the mean arterial pressure above 65 mm Hg.

The Surviving Sepsis Campaign²² recommends norepinephrine as the first-choice vasopressor, with dopamine as an alternative only in selected patients, such as those with absolute or relative bradycardia.

The guidelines also recommend epinephrine to be added to or substituted for norepinephrine when an additional catecholamine is needed to maintain adequate blood pressure.²² Furthermore, vasopressin at a dose of 0.03 units/min can be added to norepinephrine with the intent of raising the blood pressure or decreasing the norepinephrine requirement. Higher doses of vasopressin should be reserved for salvage therapy.

Regarding phenylephrine, the guidelines recommend against its use except when norepinephrine use is associated with significant tachyarrhythmias, cardiac output is known to be higher, or as a salvage therapy.²²

This is a topic of debate, with recent clinical studies offering further insight.

De Backer et al⁴⁰ compared the effects of dopamine vs norepinephrine for the treatment of shock in 1,679 patients, 62% of whom had septic shock. Overall, there was a trend towards better outcomes with norepinephrine, but no significant difference in mortality rates at 28 days (52.5% with dopamine vs 48.5% with norepinephrine, P = .10). Importantly, fewer patients who were randomized to norepinephrine developed arrhythmias (12.4% vs 24.1%, P < .001), and the norepinephrine group required fewer days of study drug (11.0 vs 12.5, P = .01) and open-label vasopressors (12.6 vs 14.2, P = .007). Of note, patients with cardiogenic shock randomized to norepinephrine had a significantly lower mortality rate than those randomized to dopamine. Although no significant difference in outcome was found between the two vasopressors in the subgroup of patients with septic shock, the overall improvements in secondary surrogate markers suggest that norepinephrine should be the first-line agent.

Norepinephrine has also been compared with “secondary” vasopressors. Annane et al,⁴¹ in a prospective multicenter randomized controlled study, evaluated the effect of norepinephrine plus dobutamine vs epinephrine alone in managing septic shock. There was no significant difference in the primary outcome measure of 28-day mortality (34% with norepinephrine plus dobutamine vs 40% with epinephrine alone, P = .31). However, the study was powered to evaluate for an absolute risk reduction of 20% in the mortality rate, which would be a big reduction. A smaller reduction in the mortality rate, which would not have been statistically significant in this study, might still be considered clinically significant. Furthermore, the group randomized to norepinephrine plus dobutamine had more vasopressor-free days (20 days vs 22 days, P = .05) and less acidosis on days 1 to 4 than the group randomized to epinephrine.

Norepinephrine was also compared with phenylephrine as a first-line vasopressor in a randomized controlled trial in 32 patients with septic shock. No difference was found in cardiopulmonary performance, global oxygen transport, or regional hemodynamics between phenylephrine and norepinephrine.⁴²

While encouraging, these preliminary data need to be verified in a larger randomized controlled trial with concrete outcome measures before being clinically adapted. Taken together, the above studies suggest that norepinephrine should be the initial vasopressor of choice for patients with septic shock.

CONTINUED MANAGEMENT OF SEPTIC SHOCK

How to manage septic shock after the initial stages is much less defined.

Uncertainty persists about the importance of achieving the early goals of resuscitation in patients who did not reach them in the initial 6 hours of treatment. Although there are data suggesting that extending the goals beyond the initial 6 hours may be beneficial, clinicians should use caution when interpreting these results in light of the observational design of the studies.^43,44 For the purpose of this discussion, “continued management” of septic shock will mean after the first 6 hours and after all the early goals are met.

The clinical decisions necessary after the initial stages of resuscitation include:

• Whether further fluid resuscitation is needed
• Assessment for further and additional hemodynamic therapies
• Consideration of adjunctive therapies
• Reevaluation of antibiotic choices (Table 2).

Is more fluid needed? How can we tell?

There is considerable debate about the ideal method for assessing fluid responsiveness. In fact, one of the criticisms of the early goal-directed therapy study²⁷ was that it used central venous pressure as a marker of fluid responsiveness.

Several studies have shown that central venous pressure or pulmonary artery occlusion pressure may not be valid measures of fluid responsiveness.⁴⁵ In fact, in a retrospective study of 150 volume challenges, the area under the receiver-operating-characteristics curve of central venous pressure as a marker of fluid responsiveness was only 0.58. (Recall that the closer the area under the curve is to 1.0, the better the test; a value of 0.50 is the same as chance.) The area under the curve for pulmonary artery occlusion pressure was 0.63.⁴⁶

In contrast, several dynamic indices have been proposed to better guide fluid resuscitation in mechanically ventilated patients.³¹ These are based on changes in stroke volume, aortic blood flow, or arterial pulse pressure in response to the ventilator cycle or passive leg-raising. A detailed review of these markers can be found elsewhere,³¹ but taken together, they have a sensitivity and specificity of over 90% for predicting fluid responsiveness. Clinicians may consider using dynamic markers of fluid responsiveness to determine when to give additional fluids, particularly after the first 6 hours of shock, in which data supporting the use of central venous pressure are lacking.

Optimal use of fluids is particularly important, since some studies suggest that “overresuscitation” has negative consequences. In a multicenter observational study of 1,177 patients with sepsis, after adjusting for a number of comorbidities and baseline severity of illness, the cumulative fluid balance in the first 72 hours after the onset of sepsis was independently associated with a worse mortality rate.⁴⁷

Furthermore, in a retrospective analysis of a randomized controlled trial of vasopressin in conjunction with norepinephrine for septic shock, patients in the highest quartile of fluid balance (more fluid in than out) at 12 hours and 4 days after presentation had significantly higher mortality rates than those in the lowest two quartiles.⁴⁸ The worse outcome with a positive fluid balance might be explained by worsening oxygenation and prolonged mechanical ventilation, as demonstrated by the Fluid and Catheter Treatment Trial in patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS).⁴⁹ Indeed, when fluid balance in patients with septic shockinduced ALI/ARDS was evaluated, patients with both adequate initial fluid resuscitation and conservative late fluid management had a lower mortality rate than those with either one alone.⁵⁰

In view of these findings, especially beyond the initial hours of resuscitation, clinicians should remember that further unnecessary fluid administration may have detrimental effects. Therefore, given the superior predictive abilities of dynamic markers of fluid responsiveness, these should be used to determine the need for further fluid boluses.

In cases in which patients are no longer fluid-responsive and need increasing levels of hemodynamic support, clinicians still have a number of options. These include increasing the current vasopressor dose or starting an additional therapy such as an alternative catecholamine vasopressor, vasopressin, inotropic therapy, or an adjunctive therapy such as a corticosteroid. The intervention could also be a combination of the above choices.

The optimal time point or vasopressor dose at which to consider initiating additional therapies is unknown. However, the Vasopressin and Septic Shock Trial (VASST) provides some insight.⁵¹

This study compared two strategies: escalating doses of norepinephrine vs adding vasopressin to norepinephrine. Overall, adding vasopressin showed no benefit in terms of a lower mortality rate. However, in the subgroup of patients with norepinephrine requirements of 5 to 14 μg/min at study enrollment (ie, a low dose, reflecting less-severe sepsis) vasopressin was associated with a lower 28-day mortality rate (26.5% vs 35.7%, P = .05) and 90-day mortality rate (35.8% vs 46.1%, P = .04). Benefit was also noted in patients with other markers of lower disease severity such as low lactate levels or having received a single vasopressor at baseline.⁵¹

Although subgroup analyses should not generally be used to guide treatment decisions, a prospective trial may never be done to evaluate adding vasopressin to catecholamines earlier vs later. Thus, clinicians who choose to use vasopressin may consider starting this therapy when catecholamine doses are relatively low or before profound hyperlactatemia from prolonged tissue hypoxia has developed.

There is less evidence to guide clinicians who are considering adding a different catecholamine. The theoretical concerns of splanchnic ischemia and cardiac arrhythmia associated with higher doses of catecholamines are usually the impetus to limit a single catecholamine to a “maximum” dose. However, studies that have evaluated combination catecholamine therapies have generally studied combinations of vasopressors with inotropes and lacked standardization in their protocols, thus making them difficult to interpret.^52–54 One could also argue that additional catecholamine therapies, which all function similarly, may have additive effects and cause even more adverse effects. As such, adding another vasopressor should be reserved for patients experiencing noticeable adverse effects (such as tachycardia) on first-line therapy.

Inotropic support

Left ventricular function should be assessed in all patients who continue to be hypotensive despite adequate fluid resuscitation and vasopressor therapy. In a study of patients with septic shock in whom echocardiography was performed daily for the first 3 days of hemodynamic support, new-onset left ventricular hypokinesia was found in 26 (39%) of 67 patients on presentation and in an additional 14 patients (21%) after at least 24 hours of norepinephrine.⁵⁵ Adding inotropic support with dobutamine or epinephrine led to decreases in vasopressor dose and enhanced left ventricular ejection fraction.

In short, left ventricular hypokinesia is common in septic shock, may occur at presentation or after a period of vasopressor support, and is usually correctable with the addition of inotropic support.

Corticosteroids

Beyond hemodynamic support with fluids and catecholamines or vasopressin (or both), clinicians should also consider adjunctive corticosteroid therapy. However, for many years the issue has been controversial for patients with severe sepsis and septic shock.

Annane et al⁵⁶ conducted a large, multicenter, randomized, double-blind, placebocontrolled trial to assess the effect of low doses of corticosteroids in patients with refractory septic shock. Overall, the 28-day mortality rate was 61% in the treatment group and 55% in the placebo group, which was not statistically significant (adjusted odds ratio 0.65, 95% confidence interval 0.39–1.07, P value .09). However, when separated by response to cosyntropin stimulation, those with a change in cortisol of 9 ug/dL or less (nonresponders) randomized to receive corticosteroids had significantly higher survival rates in the short term (28 days) and the long term (1 year). The positive results of this study led to the adoption of low-dose hydrocortisone as standard practice in most patients with septic shock.⁵⁷

But then, to evaluate the effects of corticosteroids in a broader intensive-care population with septic shock, another trial was designed: the Corticosteroid Therapy of Septic Shock (CORTICUS) trial.⁵⁸ Surprisingly, this multicenter, randomized, double-blind, placebo-controlled trial found no significant difference in survival between the group that received hydrocortisone and the placebo group, regardless of response to a cosyntropin stimulation test.

Taking into account the above studies and other randomized controlled trials, the 2012 Surviving Sepsis Campaign guidelines and the International Task Force for the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients recommend intravenous hydrocortisone therapy in adults with septic shock whose blood pressure responds poorly to fluid resuscitation and vasopressor therapy. These consensus statements do not recommend the cosyntropin stimulation test to identify patients with septic shock who should receive corticosteroids.^22,59 The guidelines, however, do not explicitly define poor response to initial therapy.

Of note, in the Annane study, which found a lower mortality rate with corticosteroids, the patients were severely ill, with a mean baseline norepinephrine dose of 1.1 μg/kg/min. In contrast, in the CORTICUS study (which found no benefit of hydrocortisone), patients had lower baseline vasopressor doses, with a mean norepinephrine dose of 0.5 μg/kg/min.

While corticosteroids are associated with a higher rate of shock reversal 7 days after initiation, ⁵⁹ this has not translated into a consistent reduction in the death rate. If a clinician is considering adding corticosteroids to decrease the risk of death, it would seem prudent to add this therapy in patients receiving norepinephrine in doses above 0.5 μg/kg/min.

The ideal sequence and combination of the above therapies including fluids, catecholamine vasopressors, vasopressin, inotropes, and vasopressors have not been elucidated. However, some preliminary evidence suggests an advantage with the combination of vasopressin and corticosteroids. In a subgroup analysis of the VASST study, in patients who received corticosteroids, the combination of vasopressin plus norepinephrine was associated with a lower 28-day mortality rate than with norepinephrine alone (35.9% vs 44.7%, P = .03).⁶⁰ These findings have been replicated in other studies,^61,62 prompting suggestions for a study of vasopressin with and without corticosteroids in patients on norepinephrine to elucidate the role of each therapy individually and in combination.

Tight glycemic control

As with corticosteroids, the pendulum for tight glycemic control in critically ill patients has swung widely in recent years. Enthusiasm was high at first after the publication of a study by van den Berghe et al, which described a 3.4% absolute reduction in mortality with intensive insulin therapy to maintain blood glucose at or below 110 mg/dL.⁶³ However, the significant benefits found in this study were never replicated.

In fact, recent evidence suggests that tight glycemic control is associated with no benefit and a higher risk of hypoglycemia.^34,64 In the largest randomized controlled trial of this topic, with more than 6,000 patients, intensive insulin therapy with a target blood glucose level of 81 to 108 mg/dL was associated with a significantly higher mortality rate (odds ratio 1.14, 95% confidence interval 1.02–1.28, P = .02) than with a target glucose level of less than 180 mg/dL.⁶⁵ Furthermore, in a recent follow-up analysis,⁶⁶ moderate hypoglycemia (serum glucose 41–70 mg/dL) and severe hypoglycemia (serum glucose < 41 mg/dL) were associated with a higher rate of death in a dose-response relationship.⁶⁶

Taking this information together, clinicians should be aware that there is no additional benefit in lowering blood glucose below the range of 140 to 180 mg/dL, and that doing so may be harmful.

Drotecogin alfa

Drotecogin alfa (Xigris) was another adjunctive therapy that has fallen from favor. It was approved for the treatment of severe sepsis in light of promising findings in initial studies.⁶⁷

However, on October 25, 2011, drotecogin alfa was voluntarily withdrawn from the market by the manufacturer after another study found no beneficial effect on the mortality rates at 28 days or at 90 days.⁶⁸ Furthermore, no difference could be found regarding any predetermined primary or secondary outcome measures.

Continued antibiotic therapy

The decision whether to continue initial empiric antimicrobial coverage, broaden it, or de-escalate must be faced for all patients with septic shock, and is ultimately clinical.

The serum procalcitonin level has been proposed to guide antibiotic discontinuation in several clinical settings, although there are still questions about the safety of such an approach. The largest randomized trial published to date reported that a procalcitoninguided strategy to treat suspected bacterial infections in nonsurgical patients could reduce antibiotic exposure with no apparent adverse outcomes.⁶⁹ On the other hand, other data discourage the use of procalcitonin-guided antimicrobial escalation, as this approach did not improve survival and worsened organ function and length of stay in the intensive care unit.⁷⁰

The Surviving Sepsis Campaign guidelines recommend combination antibiotic therapy for no longer than 3 to 5 days and limiting the duration of antibiotics in most cases to 7 to 10 days.²²

TRIALS ARE ONGOING

The understanding of the pathophysiology and treatment of sepsis has greatly advanced over the last decade. Adoption of evidence-based protocols for managing patients with septic shock has improved outcomes. Nevertheless, many multicenter trials are being conducted worldwide to look into some of the most controversial therapies, and their results will guide therapy in the future.

Considerably fewer patients who develop sepsis are dying of it now, thanks to a number of studies of how to reverse sepsis-induced tissue hypoxia.¹ The greatest strides in improving outcomes have been attributed to better early management, which includes prompt recognition of sepsis, rapid initiation of antimicrobial therapy, elimination of the source of infection, and early goal-directed therapy. Thus, even though the incidence of severe sepsis and septic shock is increasing,^2,3 the Surviving Sepsis Campaign has documented a significant decrease in unadjusted mortality rates (37% to 30.8%) associated with the bundled approach in the management of sepsis.⁴ (We will talk about this later in the article.)

This review will summarize the evidence for the early management of septic shock and will evaluate the various treatment decisions beyond the initial phases of resuscitation.

INFLAMMATION AND VASODILATION

Sepsis syndrome starts with an infection that leads to a proinflammatory state with a complex interaction between anti-inflammatory and proinflammatory mediators, enhanced coagulation, and impaired fibrinolysis.^5,6

Sepsis induces vasodilation by way of inappropriate activation of vasodilatory mechanisms (increased synthesis of nitric oxide and vasopressin deficiency) and failure of vasoconstrictor mechanisms (activation of ATP-sensitive potassium channels in vascular smooth muscle).⁷ Thus, the hemodynamic abnormalities are multifactorial, and the resultant tissue hypoperfusion further contributes to the proinflammatory and procoagulant state, precipitating multiorgan dysfunction and, often, death.

DEFINITIONS

• Sepsis—infection together with systemic manifestation of inflammatory response
• Severe sepsis—sepsis plus induced organ dysfunction or evidence of tissue hypoperfusion
• Septic shock—sepsis-induced hypotension persisting despite adequate fluid resuscitation.

EARLY MANAGEMENT OF SEPTIC SHOCK

Early in the course of septic shock, the physician’s job is to:

• Recognize it promptly
• Begin empiric antibiotic therapy quickly
• Eliminate the source of infection, if applicable, eg, by removing an infected central venous catheter
• Give fluid resuscitation, titrated to specific goals
• Give vasopressor therapy to maintain blood pressure, organ perfusion, and oxygen delivery (Table 1).

The line between “early” and “late” is not clear. Traditionally, it has been drawn at 6 hours from presentation, and this cutoff was used in some of the studies we will discuss here.

Recognizing severe sepsis early in its course

The diagnosis of severe sepsis may be challenging, since up to 40% of patients may present with cryptic shock. These patients may not be hemodynamically compromised but may show evidence of tissue hypoxia, eg, an elevated serum lactate concentration or a low central venous oxygen saturation (Scvo₂), or both.⁸ In view of this, much effort has gone into finding a biomarker that, in addition to clinical features, can help identify patients in an early stage of sepsis.

Procalcitonin levels rise in response to severe bacterial infection,⁹ and they correlate with sepsis-related organ failure scores and outcomes.^10,11 Thus, the serum procalcitonin level may help in assessing the severity of sepsis, especially when combined with standard clinical and laboratory variables. However, controversy exists about the threshold to use in making decisions about antibiotic therapy and the value of this test in differentiating severe noninfectious inflammatory reactions from infectious causes of shock.¹² Therefore, it is not widely used in clinical practice.

Serum lactate has been used for decades as a marker of tissue hypoperfusion. It is typically elevated in patients with severe sepsis and septic shock, and although the hyperlactatemia could be a result of global hypoperfusion, it can also be secondary to sepsis-induced mitochondrial dysfunction,¹³ impaired pyruvate dehydrogenase activity,¹⁴ increased aerobic glycolysis by catecholamine-stimulated sodium-potassium pump hyperactivity,¹⁵ and even impaired clearance.¹⁶

But whatever the mechanism, elevated lactate in severe sepsis and septic shock predicts a poor outcome and may help guide aggressive resuscitation. In fact, early lactate clearance (ie, normalization of an elevated value on repeat testing within the first 6 hours) is associated with better outcomes in patients with severe sepsis and septic shock.^17,18

Panels of biomarkers. A literature search revealed over 3,000 papers on 178 different biomarkers in sepsis.¹⁹ Many of these biomarkers lack sufficient specificity and sensitivity for clinical use, and thus some investigators have suggested using a panel of them to enhance their predictive ability. Shapiro et al²⁰ evaluated 971 patients admitted to the emergency department with suspected infection and discovered that a panel of three biomarkers (neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist) was highly predictive of severe sepsis, septic shock, and death.

As soon as severe sepsis and septic shock are recognized, it is imperative that adequate empiric antibiotic treatment be started, along with infectious source control if applicable.²¹ The Surviving Sepsis Campaign guidelines recommend starting intravenous antibiotics as early as possible—within the first hour of recognition of severe sepsis with or without septic shock.²²

Kumar et al,²³ in a multicenter retrospective study of patients with septic shock, found that each hour of delay in giving appropriate antimicrobial agents in the first 6 hours from the onset of hypotension was associated with a 7.6% decrease in the in-hospital survival rate.

In a similar study,²⁴ the same investigators analyzed data from 5,715 septic shock patients regarding the impact of starting the right antimicrobial therapy. Appropriate antimicrobial agents (ie, those having in vitro activity against the isolated pathogens) were given in 80.1% of cases, and the survival rate in those who received appropriate antibiotics was drastically higher than in those who received inappropriate ones (52.0% vs 10.3%, P < .0001).

In addition, two recent studies evaluated the importance of early empiric antibiotic therapy in conjunction with resuscitative protocols.^25,26 In a preplanned analysis of early antimicrobial use in a study comparing lactate clearance and Scvo₂ as goals of therapy, Puskarich et al²⁶ found that fewer patients who received antibiotics before shock was recognized (according to formal criteria) died. Similarly, in a retrospective study in patients presenting to the emergency department and treated with early goal-directed therapy (defined below), Gaieski et al²⁵ found that the mortality rate was drastically lower when antibiotics were started within 1 hour of either triage or initiation of early goal-directed therapy.

In short, it is imperative to promptly start the most appropriate broad-spectrum antibiotics to target the most likely pathogens based on site of infection, patient risk of multidrug-resistant pathogens, and local susceptibility patterns.

Goal-directed resuscitative therapy

As with antimicrobial therapy, resuscitative therapy should be started early and directed at defined goals.

Rivers et al²⁷ conducted a randomized, controlled study in patients with severe sepsis or septic shock presenting to an emergency department of an urban teaching hospital. The patients were at high risk and had either persistent hypotension after a fluid challenge or serum lactate levels of 4 mmol/L or higher.

Two hundred sixty patients were randomized to receive either early goal-directed therapy in a protocol aimed at maximizing the intravascular volume and correcting global tissue hypoxia or standard therapy in the first 6 hours after presentation. The goals in the goal-directed therapy group were:

• Central venous pressure 8 to 12 mm Hg (achieved with aggressive fluid resuscitation with crystalloids)
• Mean arterial blood pressure greater than 65 mm Hg (maintained with vasoactive drugs, if necessary)
• Scvo₂ above 70%. To achieve this third goal, packed red blood cells were infused to reach a target hematocrit of greater than 30%. For patients with a hematocrit higher than 30% but still with an Scvo₂ less than 70%, inotropic agents were added and titrated to the Scvo₂ goal of 70%.

Goal-directed therapy reduced the in-hospital mortality rate by 16% (the mortality rates were 30.5% in the goal-directed group and 46.5% in the standard therapy group, P = .009) and also reduced the 28- and 60-day mortality rates by similar proportions.²⁷

Subsequent studies of a protocol for early recognition and treatment of sepsis have concluded that early aggressive fluid resuscitation decreases the ensuing need for vasopressor support.²⁸ A resuscitation strategy based on early goal-directed therapy is a major component of the initial resuscitation bundle recommended by the Surviving Sepsis Campaign.²² (A “bundle” refers to the implementation of a core set of recommendations involving the simultaneous adaptation of a number of interventions.)

Areas of debate. However, concerns have been raised about the design of the study by Rivers et al and the mortality rate in the control group, which was higher than one would expect from the patients’ Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.²⁹ In particular, the bundled approach they used precludes the ability to differentiate which interventions were responsible for the outcome benefits. Indeed, there were two major interventions in the early goal-directed therapy group: a protocol for achieving the goals described and the use of Scvo₂ as a goal.

Aggressive fluid resuscitation is considered the most critical aspect of all the major interventions, and there is little argument on its value. The debate centers on central venous pressure as a preload marker, since after the publication of the early goal-directed therapy trial,²⁷ several studies showed that central venous pressure may not be a valid measure to predict fluid responsiveness (discussed later in this paper).^30,31

The choice of colloids or crystalloids for fluid resuscitation is another area of debate. Clinical evidence suggests that albumin is equivalent to normal saline in a heterogeneous intensive care unit population,³² but subgroup analyses suggest albumin may be superior in patients with septic shock.³³ Studies are ongoing (NCT00707122, NCT01337934, and NCT00318942). The use of hydroxyethyl starch in severe sepsis is associated with higher rates of acute renal failure and need for renal replacement therapy than Ringer’s lactate,³⁴ and is generally not recommended. This is further substantiated by two recent randomized controlled studies, which found that the use of hydroxyethyl starch for fluid resuscitation in severe sepsis, compared with crystalloids, did not reduce the mortality rate (and even increased it in one study), and was associated with more need for renal replacement therapy.^35,36

The use of Scvo₂ is yet another topic of debate, and other monitoring variables have been evaluated. A recent study assessed the noninferiority of incorporating venous lactate clearance into the early goal-directed therapy protocol vs Scvo₂.³⁷ Both groups had identical goals for central venous pressure and mean arterial pressure but differed in the use of lactate clearance (defined as at least a 10% decline) or Scvo₂ (> 70%) as the goal for improving tissue hypoxia. There were no significant differences between groups in their in-hospital mortality rates (17% in the lactate clearance group vs 23% in the Scvo₂ group; criteria for noninferiority met). This suggests that lactate may be an alternative to Scvo₂ as a goal in early goal-directed therapy. However, a secondary analysis of the data revealed a lack of concordance in achieving lactate clearance and Scvo₂ goals, which suggests that these parameters may be measuring distinct physiologic processes.³⁸ Since the hemodynamic profiles of septic shock patients are complex, it may be prudent to use both of these markers of resuscitation until further studies are completed.

Given the debate, a number of prospective randomized trials are under way to evaluate resuscitative interventions. These include the Protocolized Care for Early Septic Shock trial (NCT00510835), the Australasian Resuscitation in Sepsis Evaluation trial (NCT00975793), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (ISRCTN 36307479). These three trials will evaluate, collectively, close to 4,000 patients and will provide considerable insights into resuscitative interventions in septic shock.

If fluid therapy does not restore perfusion, vasopressors should be promptly initiated, as the longer that hypotension goes on, the lower the survival rate.³⁹

But which vasopressor should be used? The early goal-directed therapy protocol used in the study by Rivers et al²⁷ did not specify which vasopressor should be used to keep the mean arterial pressure above 65 mm Hg.

The Surviving Sepsis Campaign²² recommends norepinephrine as the first-choice vasopressor, with dopamine as an alternative only in selected patients, such as those with absolute or relative bradycardia.

The guidelines also recommend epinephrine to be added to or substituted for norepinephrine when an additional catecholamine is needed to maintain adequate blood pressure.²² Furthermore, vasopressin at a dose of 0.03 units/min can be added to norepinephrine with the intent of raising the blood pressure or decreasing the norepinephrine requirement. Higher doses of vasopressin should be reserved for salvage therapy.

Regarding phenylephrine, the guidelines recommend against its use except when norepinephrine use is associated with significant tachyarrhythmias, cardiac output is known to be higher, or as a salvage therapy.²²

This is a topic of debate, with recent clinical studies offering further insight.

De Backer et al⁴⁰ compared the effects of dopamine vs norepinephrine for the treatment of shock in 1,679 patients, 62% of whom had septic shock. Overall, there was a trend towards better outcomes with norepinephrine, but no significant difference in mortality rates at 28 days (52.5% with dopamine vs 48.5% with norepinephrine, P = .10). Importantly, fewer patients who were randomized to norepinephrine developed arrhythmias (12.4% vs 24.1%, P < .001), and the norepinephrine group required fewer days of study drug (11.0 vs 12.5, P = .01) and open-label vasopressors (12.6 vs 14.2, P = .007). Of note, patients with cardiogenic shock randomized to norepinephrine had a significantly lower mortality rate than those randomized to dopamine. Although no significant difference in outcome was found between the two vasopressors in the subgroup of patients with septic shock, the overall improvements in secondary surrogate markers suggest that norepinephrine should be the first-line agent.

Norepinephrine has also been compared with “secondary” vasopressors. Annane et al,⁴¹ in a prospective multicenter randomized controlled study, evaluated the effect of norepinephrine plus dobutamine vs epinephrine alone in managing septic shock. There was no significant difference in the primary outcome measure of 28-day mortality (34% with norepinephrine plus dobutamine vs 40% with epinephrine alone, P = .31). However, the study was powered to evaluate for an absolute risk reduction of 20% in the mortality rate, which would be a big reduction. A smaller reduction in the mortality rate, which would not have been statistically significant in this study, might still be considered clinically significant. Furthermore, the group randomized to norepinephrine plus dobutamine had more vasopressor-free days (20 days vs 22 days, P = .05) and less acidosis on days 1 to 4 than the group randomized to epinephrine.

Norepinephrine was also compared with phenylephrine as a first-line vasopressor in a randomized controlled trial in 32 patients with septic shock. No difference was found in cardiopulmonary performance, global oxygen transport, or regional hemodynamics between phenylephrine and norepinephrine.⁴²

While encouraging, these preliminary data need to be verified in a larger randomized controlled trial with concrete outcome measures before being clinically adapted. Taken together, the above studies suggest that norepinephrine should be the initial vasopressor of choice for patients with septic shock.

CONTINUED MANAGEMENT OF SEPTIC SHOCK

How to manage septic shock after the initial stages is much less defined.

Uncertainty persists about the importance of achieving the early goals of resuscitation in patients who did not reach them in the initial 6 hours of treatment. Although there are data suggesting that extending the goals beyond the initial 6 hours may be beneficial, clinicians should use caution when interpreting these results in light of the observational design of the studies.^43,44 For the purpose of this discussion, “continued management” of septic shock will mean after the first 6 hours and after all the early goals are met.

The clinical decisions necessary after the initial stages of resuscitation include:

• Whether further fluid resuscitation is needed
• Assessment for further and additional hemodynamic therapies
• Consideration of adjunctive therapies
• Reevaluation of antibiotic choices (Table 2).

Is more fluid needed? How can we tell?

There is considerable debate about the ideal method for assessing fluid responsiveness. In fact, one of the criticisms of the early goal-directed therapy study²⁷ was that it used central venous pressure as a marker of fluid responsiveness.

Several studies have shown that central venous pressure or pulmonary artery occlusion pressure may not be valid measures of fluid responsiveness.⁴⁵ In fact, in a retrospective study of 150 volume challenges, the area under the receiver-operating-characteristics curve of central venous pressure as a marker of fluid responsiveness was only 0.58. (Recall that the closer the area under the curve is to 1.0, the better the test; a value of 0.50 is the same as chance.) The area under the curve for pulmonary artery occlusion pressure was 0.63.⁴⁶

In contrast, several dynamic indices have been proposed to better guide fluid resuscitation in mechanically ventilated patients.³¹ These are based on changes in stroke volume, aortic blood flow, or arterial pulse pressure in response to the ventilator cycle or passive leg-raising. A detailed review of these markers can be found elsewhere,³¹ but taken together, they have a sensitivity and specificity of over 90% for predicting fluid responsiveness. Clinicians may consider using dynamic markers of fluid responsiveness to determine when to give additional fluids, particularly after the first 6 hours of shock, in which data supporting the use of central venous pressure are lacking.

Optimal use of fluids is particularly important, since some studies suggest that “overresuscitation” has negative consequences. In a multicenter observational study of 1,177 patients with sepsis, after adjusting for a number of comorbidities and baseline severity of illness, the cumulative fluid balance in the first 72 hours after the onset of sepsis was independently associated with a worse mortality rate.⁴⁷

Furthermore, in a retrospective analysis of a randomized controlled trial of vasopressin in conjunction with norepinephrine for septic shock, patients in the highest quartile of fluid balance (more fluid in than out) at 12 hours and 4 days after presentation had significantly higher mortality rates than those in the lowest two quartiles.⁴⁸ The worse outcome with a positive fluid balance might be explained by worsening oxygenation and prolonged mechanical ventilation, as demonstrated by the Fluid and Catheter Treatment Trial in patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS).⁴⁹ Indeed, when fluid balance in patients with septic shockinduced ALI/ARDS was evaluated, patients with both adequate initial fluid resuscitation and conservative late fluid management had a lower mortality rate than those with either one alone.⁵⁰

In view of these findings, especially beyond the initial hours of resuscitation, clinicians should remember that further unnecessary fluid administration may have detrimental effects. Therefore, given the superior predictive abilities of dynamic markers of fluid responsiveness, these should be used to determine the need for further fluid boluses.

In cases in which patients are no longer fluid-responsive and need increasing levels of hemodynamic support, clinicians still have a number of options. These include increasing the current vasopressor dose or starting an additional therapy such as an alternative catecholamine vasopressor, vasopressin, inotropic therapy, or an adjunctive therapy such as a corticosteroid. The intervention could also be a combination of the above choices.

The optimal time point or vasopressor dose at which to consider initiating additional therapies is unknown. However, the Vasopressin and Septic Shock Trial (VASST) provides some insight.⁵¹

This study compared two strategies: escalating doses of norepinephrine vs adding vasopressin to norepinephrine. Overall, adding vasopressin showed no benefit in terms of a lower mortality rate. However, in the subgroup of patients with norepinephrine requirements of 5 to 14 μg/min at study enrollment (ie, a low dose, reflecting less-severe sepsis) vasopressin was associated with a lower 28-day mortality rate (26.5% vs 35.7%, P = .05) and 90-day mortality rate (35.8% vs 46.1%, P = .04). Benefit was also noted in patients with other markers of lower disease severity such as low lactate levels or having received a single vasopressor at baseline.⁵¹

Although subgroup analyses should not generally be used to guide treatment decisions, a prospective trial may never be done to evaluate adding vasopressin to catecholamines earlier vs later. Thus, clinicians who choose to use vasopressin may consider starting this therapy when catecholamine doses are relatively low or before profound hyperlactatemia from prolonged tissue hypoxia has developed.

There is less evidence to guide clinicians who are considering adding a different catecholamine. The theoretical concerns of splanchnic ischemia and cardiac arrhythmia associated with higher doses of catecholamines are usually the impetus to limit a single catecholamine to a “maximum” dose. However, studies that have evaluated combination catecholamine therapies have generally studied combinations of vasopressors with inotropes and lacked standardization in their protocols, thus making them difficult to interpret.^52–54 One could also argue that additional catecholamine therapies, which all function similarly, may have additive effects and cause even more adverse effects. As such, adding another vasopressor should be reserved for patients experiencing noticeable adverse effects (such as tachycardia) on first-line therapy.

Inotropic support

Left ventricular function should be assessed in all patients who continue to be hypotensive despite adequate fluid resuscitation and vasopressor therapy. In a study of patients with septic shock in whom echocardiography was performed daily for the first 3 days of hemodynamic support, new-onset left ventricular hypokinesia was found in 26 (39%) of 67 patients on presentation and in an additional 14 patients (21%) after at least 24 hours of norepinephrine.⁵⁵ Adding inotropic support with dobutamine or epinephrine led to decreases in vasopressor dose and enhanced left ventricular ejection fraction.

In short, left ventricular hypokinesia is common in septic shock, may occur at presentation or after a period of vasopressor support, and is usually correctable with the addition of inotropic support.

Corticosteroids

Beyond hemodynamic support with fluids and catecholamines or vasopressin (or both), clinicians should also consider adjunctive corticosteroid therapy. However, for many years the issue has been controversial for patients with severe sepsis and septic shock.

Annane et al⁵⁶ conducted a large, multicenter, randomized, double-blind, placebocontrolled trial to assess the effect of low doses of corticosteroids in patients with refractory septic shock. Overall, the 28-day mortality rate was 61% in the treatment group and 55% in the placebo group, which was not statistically significant (adjusted odds ratio 0.65, 95% confidence interval 0.39–1.07, P value .09). However, when separated by response to cosyntropin stimulation, those with a change in cortisol of 9 ug/dL or less (nonresponders) randomized to receive corticosteroids had significantly higher survival rates in the short term (28 days) and the long term (1 year). The positive results of this study led to the adoption of low-dose hydrocortisone as standard practice in most patients with septic shock.⁵⁷

But then, to evaluate the effects of corticosteroids in a broader intensive-care population with septic shock, another trial was designed: the Corticosteroid Therapy of Septic Shock (CORTICUS) trial.⁵⁸ Surprisingly, this multicenter, randomized, double-blind, placebo-controlled trial found no significant difference in survival between the group that received hydrocortisone and the placebo group, regardless of response to a cosyntropin stimulation test.

Taking into account the above studies and other randomized controlled trials, the 2012 Surviving Sepsis Campaign guidelines and the International Task Force for the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients recommend intravenous hydrocortisone therapy in adults with septic shock whose blood pressure responds poorly to fluid resuscitation and vasopressor therapy. These consensus statements do not recommend the cosyntropin stimulation test to identify patients with septic shock who should receive corticosteroids.^22,59 The guidelines, however, do not explicitly define poor response to initial therapy.

Of note, in the Annane study, which found a lower mortality rate with corticosteroids, the patients were severely ill, with a mean baseline norepinephrine dose of 1.1 μg/kg/min. In contrast, in the CORTICUS study (which found no benefit of hydrocortisone), patients had lower baseline vasopressor doses, with a mean norepinephrine dose of 0.5 μg/kg/min.

While corticosteroids are associated with a higher rate of shock reversal 7 days after initiation, ⁵⁹ this has not translated into a consistent reduction in the death rate. If a clinician is considering adding corticosteroids to decrease the risk of death, it would seem prudent to add this therapy in patients receiving norepinephrine in doses above 0.5 μg/kg/min.

The ideal sequence and combination of the above therapies including fluids, catecholamine vasopressors, vasopressin, inotropes, and vasopressors have not been elucidated. However, some preliminary evidence suggests an advantage with the combination of vasopressin and corticosteroids. In a subgroup analysis of the VASST study, in patients who received corticosteroids, the combination of vasopressin plus norepinephrine was associated with a lower 28-day mortality rate than with norepinephrine alone (35.9% vs 44.7%, P = .03).⁶⁰ These findings have been replicated in other studies,^61,62 prompting suggestions for a study of vasopressin with and without corticosteroids in patients on norepinephrine to elucidate the role of each therapy individually and in combination.

Tight glycemic control

As with corticosteroids, the pendulum for tight glycemic control in critically ill patients has swung widely in recent years. Enthusiasm was high at first after the publication of a study by van den Berghe et al, which described a 3.4% absolute reduction in mortality with intensive insulin therapy to maintain blood glucose at or below 110 mg/dL.⁶³ However, the significant benefits found in this study were never replicated.

In fact, recent evidence suggests that tight glycemic control is associated with no benefit and a higher risk of hypoglycemia.^34,64 In the largest randomized controlled trial of this topic, with more than 6,000 patients, intensive insulin therapy with a target blood glucose level of 81 to 108 mg/dL was associated with a significantly higher mortality rate (odds ratio 1.14, 95% confidence interval 1.02–1.28, P = .02) than with a target glucose level of less than 180 mg/dL.⁶⁵ Furthermore, in a recent follow-up analysis,⁶⁶ moderate hypoglycemia (serum glucose 41–70 mg/dL) and severe hypoglycemia (serum glucose < 41 mg/dL) were associated with a higher rate of death in a dose-response relationship.⁶⁶

Taking this information together, clinicians should be aware that there is no additional benefit in lowering blood glucose below the range of 140 to 180 mg/dL, and that doing so may be harmful.

Drotecogin alfa

Drotecogin alfa (Xigris) was another adjunctive therapy that has fallen from favor. It was approved for the treatment of severe sepsis in light of promising findings in initial studies.⁶⁷

However, on October 25, 2011, drotecogin alfa was voluntarily withdrawn from the market by the manufacturer after another study found no beneficial effect on the mortality rates at 28 days or at 90 days.⁶⁸ Furthermore, no difference could be found regarding any predetermined primary or secondary outcome measures.

Continued antibiotic therapy

The decision whether to continue initial empiric antimicrobial coverage, broaden it, or de-escalate must be faced for all patients with septic shock, and is ultimately clinical.

The serum procalcitonin level has been proposed to guide antibiotic discontinuation in several clinical settings, although there are still questions about the safety of such an approach. The largest randomized trial published to date reported that a procalcitoninguided strategy to treat suspected bacterial infections in nonsurgical patients could reduce antibiotic exposure with no apparent adverse outcomes.⁶⁹ On the other hand, other data discourage the use of procalcitonin-guided antimicrobial escalation, as this approach did not improve survival and worsened organ function and length of stay in the intensive care unit.⁷⁰

The Surviving Sepsis Campaign guidelines recommend combination antibiotic therapy for no longer than 3 to 5 days and limiting the duration of antibiotics in most cases to 7 to 10 days.²²

TRIALS ARE ONGOING

The understanding of the pathophysiology and treatment of sepsis has greatly advanced over the last decade. Adoption of evidence-based protocols for managing patients with septic shock has improved outcomes. Nevertheless, many multicenter trials are being conducted worldwide to look into some of the most controversial therapies, and their results will guide therapy in the future.

Cardiac tamponade is a life-threatening condition that can be palliated or cured, depending on its cause and on the timeliness of treatment. Making a timely diagnosis and providing the appropriate treatment can be gratifying for both patient and physician.

Cardiac tamponade occurs when fluid in the pericardial space reaches a pressure exceeding central venous pressure. This leads to jugular venous distention, visceral organ engorgement, edema, and elevated pulmonary venous pressure that causes dyspnea. Despite compensatory tachycardia, the decrease in cardiac filling leads to a fall in cardiac output and to arterial hypoperfusion of vital organs.

PEARL 1: SLOW ACCUMULATION LEADS TO EDEMA

The rate at which pericardial fluid accumulates influences the clinical presentation of cardiac tamponade, in particular whether or not there is edema. Whereas rapid accumulation is characterized more by hypotension than by edema, the slow accumulation of pericardial fluid affords the patient time to drink enough liquid to keep the central venous pressure higher than the rising pericardial pressure. Thus, edema and dyspnea are more prominent features of cardiac tamponade when there is a slow rise in pericardial pressure.

PEARL 2: EDEMA IS NOT ALWAYS TREATED WITH A DIURETIC

Edema is not always treated with a diuretic. In a patient who has a pericardial effusion that has developed slowly and who has been drinking enough fluid to keep the central venous pressure higher than the pericardial pressure, a diuretic can remove enough volume from the circulation to lower the central venous pressure below the intrapericardial pressure and thus convert a benign pericardial effusion to potentially lethal cardiac tamponade.

One must understand the cause of edema or low urine output before treating it. This underscores the importance of the history and the physical examination. All of the following must be assessed:

• Symptoms and time course of the illness
• Concurrent medical illnesses
• Neck veins
• Blood pressure and its response to inspiration
• Heart sounds
• Heart rate and rhythm
• Abdominal organ engorgement
• Edema (or its absence).

PEARL 3: UNDERSTANDING THE CAUSE IS ESSENTIAL

Understanding the cause of cardiac tamponade is essential.

A trauma patient first encountered in the emergency department may have an underlying disease, but the focus is squarely on the effects of trauma or violent injury. In a patient with multiple trauma, hypotension and tachycardia that do not respond to intravenous volume replacement when there is an obvious rise in central venous pressure should be clues to cardiac tamponade.¹

If the patient has recently undergone a cardiac procedure (for example, cardiac surgery, myocardial biopsy, coronary intervention, electrophysiologic study with intracardiac electrodes, transvenous pacemaker placement, pacemaker lead extraction, or radiofrequency ablation), knowing about the procedure narrows the differential diagnosis when hypotension, tachycardia, and jugular venous distention develop.

PEARL 4: CARDIAC OR AORTIC RUPTURE REQUIRES SURGERY

When the etiology of cardiac tamponade is cardiac or aortic rupture, the treatment is surgical.

Painful sudden causes of cardiac tamponade include hemopericardium due to rupture of the free wall after myocardial infarction, and spontaneous or posttraumatic dissection and rupture of the ascending aorta. Prompt diagnosis is necessary, but since these lesions will not close and heal spontaneously, the definitive treatment should be surgery. Moreover, needle removal of intrapericardial blood that has been opposing further bleeding is sure to permit bleeding to recur, often with lethal consequences.²

Causes of cardiac tamponade that have a less-acute onset are likely to be complications of medical problems. Medical illnesses known to be associated with cardiac tamponade include:

• Infectious disease (idiopathic or viral, associated with smallpox vaccination, mycobacterial, purulent bacterial, fungal)
• Metastatic cancer (lung, breast, esophagus, lymphoma, pancreas, liver, leukemia, stomach, melanoma)³
• Connective tissue disease (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, Wegener granulomatosis, acute rheumatic fever)
• Endocrine disease (hypothyroidism)
• Drug side effects (procainamide, isoniazid, hydralazine, minoxidil, phenytoin, anticoagulants, methysergide)
• Inflammatory bowel disease (Crohn disease, ulcerative colitis)
• Congestive heart failure
• Uremia
• Radiation therapy
• Postmyocardial infarction syndrome (Dressler syndrome)
• Postpericardiotomy syndrome.

PEARL 5: REVIEW IMAGING BEFORE DIAGNOSING

What often brings a patient with cardiac tamponade to the attention of the physician is a finding on echocardiography, computed tomography, or magnetic resonance imaging of the chest.

Always review the imaging studies before making the diagnosis of cardiac tamponade. These tests must be reviewed to assess the anatomy and the size and location of the effusion. Particularly, one must look for atrial and right ventricular collapse and inferior vena caval plethora, which are echocardiographic signs of cardiac tamponade.⁴ Figures 1, 2, and 3 show imaging studies in a patient who presented with worsening cough 2 weeks after undergoing a cardiac procedure and who was found to have cardiac tamponade.

When the history and these imaging studies place cardiac tamponade high in the differential diagnosis as the cause of edema or dyspnea, it is time to reexamine the patient. The best first step is to measure pulsus paradoxus.

HOW PULSUS PARADOXUS OCCURS

To fully appreciate the subtleties of the next pearls, it is necessary to understand the pathophysiology of cardiac tamponade.

When pericardial fluid accumulation raises the pericardial pressure above the central venous pressure and pulmonary venous pressure (intravascular pressure), blood will not passively return to the right side of the heart from the venae cavae nor to the left side of the heart from the pulmonary veins unless it is influenced by the effects of respiration on intrathoracic pressure. During respiration, the right and left sides of the heart are alternately filled and deprived of their respective venous return.

During inspiration, as the intrathoracic pressure decreases, blood in the venae cavae empties into the right side of the heart, while blood in the pulmonary veins preferentially remains in the pulmonary veins, underfilling the left side of the heart. Since the right ventricle is more filled than the left ventricle during inspiration, the ventricular septum shifts from right to left, further opposing pulmonary venous return. As a result, during cardiac tamponade, the systemic blood pressure falls with inspiration.

During expiration the opposite occurs. Expiration decreases the intrathoracic volume, so the intrathoracic pressure rises. This tends to oppose vena caval return to the right side of the heart and to favor pulmonary venous return to the left side of the heart. The ventricular septum shifts from left to right, further accommodating left ventricular filling, raising stroke volume, and increasing blood pressure. This exaggerated alternate filling of the right and left sides of the heart during cardiac tamponade is what accounts for pulsus paradoxus, an inspiratory fall in systolic blood pressure of greater than 10 mm Hg.

If intravascular pressure is low (due to hemorrhage, dehydration, or diuretic therapy), the pressure in the pericardial space needed to oppose venous return is much less. In this low-pressure scenario, the results are low cardiac output and hypotension, which are treated by giving intravenous fluids to maintain intravascular volume.

PEARL 6: MEASURE PULSUS PARADOXUS

When cardiac tamponade is considered, one must always measure the pulsus paradoxus.

The term pulsus paradoxus was coined by Adolph Kussmaul in 1873, before physicians could even measure blood pressure. All they could do at that time was palpate the pulse and listen to the heart. Kussmaul described his observation as a conspicuous discrepancy between the cardiac action and the arterial pulse.

Although not described by Kussmaul, another explanation for this finding might be more suited to the use of the word “paradoxical.” When the pulse is palpated in a normal patient, with inspiration the pulse rate will increase via the Bainbridge reflex, and with expiration it will decrease. But in a patient with cardiac tamponade, there is a paradoxical inspiratory slowing of the pulse (because the decreased magnitude of the pulse at times makes it imperceptible) and an expiratory increase in pulse rate as the magnitude of the pulse again makes it palpable.

The magnitude of the fall in systolic blood pressure during inspiration has been used to estimate the level of hemodynamic impairment resulting from pericardial effusion.⁵ A rapidly accumulating pericardial effusion can have more hemodynamic impact than a much larger one that accumulates slowly. Thus, the intrapericardial pressure must be considered more than the volume of pericardial fluid.

When there is severe cardiac tamponade and overt pulsus paradoxus, simple palpation of a proximal arterial pulse can detect a marked inspiratory decrease or loss of the pulse, which returns with expiration. Tachycardia is almost always present, unless the cause is hypothyroidism.⁶

How to measure pulsus paradoxus with a manual sphygmomanometer

A stethoscope and manual sphygmomanometer are all that is needed to measure pulsus paradoxus. A noninvasive blood pressure monitor that averages multiple measurements cannot detect or quantify pulsus paradoxus.

The patient should be supine with the head elevated 30° to 45°, and the examiner should be seated comfortably at the patient’s side. The manometer should be on the opposite side of the patient in plain view of the examiner. Position the cuff on the arm above the elbow and place your stethoscope on the antecubital fossa. Then:

• Inflate the cuff 20 mm Hg above the highest systolic pressure previously auscultated.
• Slowly decrease the manometer pressure by 5 mm Hg and hold it there through two or three respiratory cycles while listening for the first Korotkoff (systolic) sound. Repeat this until you can hear the systolic sound (but only during expiration) and mentally note the pressure.
• Continue to decrease the manometer pressure by 5-mm Hg increments while listening. When the Korotkoff sounds no longer disappear with inspiration, mentally note this second value as well. The pulsus paradoxus is the difference between these values.
• When the Korotkoff sounds disappear as the manometer pressure is decreased, note this final value. This is the diastolic blood pressure.

PEARL 7: THE PLETHYSMOGRAM WAVE-FORM PARALLELS PULSUS PARADOXUS

Manual measurement of blood pressure and pulsus paradoxus can be difficult, especially in an obese patient or one with a fat-distorted arm on which the cuff does not maintain its position. In such patients, increased girth of the neck and abdomen also make it difficult to assess the jugular venous distention and visceral organ engorgement that characterize cardiac tamponade.

When the use of a sphygmomanometer is not possible, an arterial catheter can be inserted to demonstrate pulsus paradoxus. Simpler, however, is the novel use of another noninvasive instrument to detect and coarsely quantify pulsus paradoxus.⁷ The waveform on finger pulse oximetry can demonstrate pulsus paradoxus. The plethysmogram of the finger pulse oximeter can demonstrate the decrease in magnitude of the waveform with each inspiration (Figure 4).

Caution must be taken when interpreting this waveform, as with any measurement of pulsus paradoxus, to exclude a concomitant arrhythmia.

PEARL 8: PULSUS PARADOXUS WITHOUT CARDIAC TAMPONADE

Pulsus paradoxus can be present in the absence of cardiac tamponade. Once pulsus paradoxus of more than 10 mm Hg is measured, one must be sure the patient does not have a condition that can cause pulsus paradoxus without cardiac tamponade. Most of these are pulmonary conditions that necessitate an exaggerated inspiratory effort that can lower intrathoracic pressure sufficiently to oppose pulmonary venous return and cause a fall in systemic blood pressure:

• Chronic bronchitis
• Emphysema
• Mucus plug
• Pneumothorax
• Pulmonary embolism
• Stridor.

In these, there may be pulsus paradoxus, but not due to cardiac tamponade.

PEARL 9: CARDIAC TAMPONADE CAN BE PRESENT WITHOUT PULSUS PARADOXUS

Cardiac tamponade can be present without pulsus paradoxus. This occurs when certain conditions prevent inspiratory underfilling of the left ventricle relative to the filling of the right ventricle.⁸

How does this work? In cardiac tamponade, factors that drive the exaggerated fall in arterial pressure with inspiration (pulsus paradoxus) are the augmented right ventricular filling and the decreased left ventricular filling, both due to the lowering of the intrathoracic pressure. As the vena caval emptying is augmented, the right ventricular filling is increased, the ventricular septum shifts to the left, and pulmonary venous return to the heart is decreased.

Factors that can oppose pulsus paradoxus:

• Positive pressure ventilation prevents pulsus paradoxus by preventing the fall in intrathoracic pressure.
• Severe aortic regurgitation does not permit underfilling of the left ventricle during inspiration.
• An atrial septal defect will always equalize the right and left atrial pressures, preventing differential right ventricular and left ventricular filling with inspiration.
• Severe left ventricular hypertrophy does not permit the inspiratory shift of the ventricular septum from right to left that would otherwise lead to decreased left ventricular filling.
• Severe left ventricular dysfunction, with its low stroke volume and severe elevation of left ventricular end-diastolic pressure, never permits underfilling of the left ventricle, despite cardiac tamponade and an inspiratory decrease in intrathoracic pressure.
• Intravascular volume depletion due to hemorrhage, hemodialysis, or mistaken use of diuretics to treat edema can cause marked hypotension, making pulsus paradoxus impossible to detect.

Knowledge of underlying medical conditions, the likelihood of their causing cardiac tamponade, and the appearance of the echocardiogram prompt the physician to look further when the presence or absence of pulsus paradoxus does not fit with the working diagnosis.

The echocardiogram can give hints to the etiology of a pericardial effusion, such as clotted blood after trauma or a cardiac-perforating procedure, tumor studding of the epicardium,⁹ or fibrin strands indicating chronicity or an inflammatory process.¹⁰ Diastolic collapse of the right ventricle, more than collapse of the right atrium or left atrium, speaks for the severity of cardiac tamponade. With hemodynamically significant pericardial effusion and cardiac tamponade, the inferior vena cava is distended and does not decrease in size with inspiration unless there is severe intravascular volume depletion, at which time the inferior vena cava is underfilled throughout the respiratory cycle.

PEARL 10: PLAN HOW TO DRAIN

The size and location of the pericardial effusion and the patient’s hemodynamics must be integrated when deciding how to relieve cardiac tamponade. When cardiac tamponade is indeed severe and the patient and physician agree that it must be drained, the options are percutaneous needle aspiration (pericardiocentesis) and surgical pericardiostomy (creation of a pericardial window). Here again, as assessed by echocardiography, the access to the pericardial fluid should influence the choice.

Pericardiocentesis can be safely done if certain criteria are met. The patient must be able to lie still in the supine position, perhaps with the head of the bed elevated 30 degrees. Anticoagulation must be reversed or allowed time to resolve if drainage is not an emergency.

Pericardiocentesis can be risky or unsuccessful if there is not enough pericardial fluid to permit respiratory cardiac motion without perforating the heart with the needle; if the effusion is loculated (confined to a pocket) posteriorly; or if it is too far from the skin to permit precise control and placement of a spinal needle into the pericardial space. In cases of cardiac tamponade in which the anatomy indicates surgical pericardiostomy but severe hypotension prevents the induction of anesthesia and positive-pressure ventilation—which can result in profound, irreversible hypotension—percutaneous needle drainage (pericardiocentesis) should be performed in the operating room to relieve the tamponade before the induction of anesthesia and the surgical drainage.¹¹

To reiterate, a suspected cardiac or aortic rupture that causes cardiac tamponade is usually large and not apt to self-seal. In such cases, the halt in the accumulation of pericardial blood is due to hypotension and not due to spontaneous resolution. Open surgical drainage is required from the outset because an initial success of pericardiocentesis yields to the recurrence of cardiac tamponade.

PEARL 11: ANTICIPATE WHAT THE FLUID SHOULD LOOK LIKE

Before performing pericardiocentesis, anticipate the appearance of the pericardial fluid on the basis of the presumed etiology, ie:

• Sanguinous—trauma, heart surgery, cardiac perforation from a procedure, anticoagulation, uremia, or malignancy
• Serous—congestive heart failure, acute radiation therapy
• Purulent—infections (natural or postoperative)
• Turbid (like gold paint)—mycobacterial infection, rheumatoid arthritis, myxedema
• Chylous—pericardium fistulized to the thoracic duct by a natural or postsurgical cause.

Sanguinous pericardial effusion encountered during a pericardiocentesis, if not anticipated, can be daunting and can cause the operator to question if it is the result of inadvertent needle placement in a cardiac chamber. If the needle is indeed in the heart, blood often surges out under pressure in pulses, which strongly suggests that the needle is not in the pericardial space and should be removed; but if confirmation of the location is needed before removing the needle, it can be done by injecting 2 mL of agitated sterile saline through the pericardiocentesis needle during echocardiographic imaging.¹²

Before inserting the needle, the ideal access location and needle angle must be determined by the operator with echocardiographic transducer in hand. The distance from skin to a point just through the parietal pericardium can also be measured at this time.

Once the needle is in the pericardial fluid (and you are confident of its placement), removal of 50 to 100 mL of the fluid with a large syringe can be enough to afford the patient easier breathing, higher blood pressure, and lower pulsus paradoxus—and even the physician will breathe easier. The same syringe can be filled and emptied multiple times. Less traumatic and more complete removal of pericardial fluid requires insertion of a multihole pigtail catheter over a J-tipped guidewire that is introduced through the needle.

PEARL 12: DRAIN SLOWLY TO AVOID PULMONARY EDEMA

Pulmonary edema is an uncommon complication of pericardiocentesis that might be avoidable. Heralded by sudden coughing and pink, frothy sputum, it can rapidly deteriorate into respiratory failure. The mechanism has been attributed to a sudden increase in right ventricular stroke volume and resultant left ventricular filling after the excess pericardial fluid has been removed, before the systemic arteries, which constrict to keep the systemic blood pressure up during cardiac tamponade, have had time to relax.¹³

To avoid this complication, if the volume of pericardial fluid responsible for cardiac tamponade is large, it should be removed slowly,¹⁴ stopping for a several-minute rest after each 250 mL. Catheter removal of pericardial fluid by gravity drainage over 24 hours has been suggested.¹⁵ A drawback to this approach is catheter clotting or sludging before all the fluid has been removed. It is helpful to keep the drainage catheter close to the patient’s body temperature to make the fluid less viscous. Output should be monitored hourly.

When the pericardial fluid has been completely drained, one must decide how long to leave the catheter in. One reason to remove the catheter at this time is that it causes pleuritic pain; another is to avoid introducing infection. A reason to leave the catheter in is to observe the effect of medical treatment on the hourly pericardial fluid output. Nonsteroidal anti-inflammatory drugs are the drugs of first choice when treating pericardial inflammation and suppressing production of pericardial fluid.¹⁶ In most cases the catheter should not be left in place for more than 3 days.

Laboratory analysis of the pericardial fluid should shed light on its suspected cause. Analysis usually involves chemistry testing, microscopic inspection of blood cell smears, cytology, microbiologic stains and cultures, and immunologic tests. Results often take days. Meyers and colleagues¹⁷ expound on this subject.

Cardiac tamponade is a life-threatening condition that can be palliated or cured, depending on its cause and on the timeliness of treatment. Making a timely diagnosis and providing the appropriate treatment can be gratifying for both patient and physician.

Cardiac tamponade occurs when fluid in the pericardial space reaches a pressure exceeding central venous pressure. This leads to jugular venous distention, visceral organ engorgement, edema, and elevated pulmonary venous pressure that causes dyspnea. Despite compensatory tachycardia, the decrease in cardiac filling leads to a fall in cardiac output and to arterial hypoperfusion of vital organs.

PEARL 1: SLOW ACCUMULATION LEADS TO EDEMA

The rate at which pericardial fluid accumulates influences the clinical presentation of cardiac tamponade, in particular whether or not there is edema. Whereas rapid accumulation is characterized more by hypotension than by edema, the slow accumulation of pericardial fluid affords the patient time to drink enough liquid to keep the central venous pressure higher than the rising pericardial pressure. Thus, edema and dyspnea are more prominent features of cardiac tamponade when there is a slow rise in pericardial pressure.

PEARL 2: EDEMA IS NOT ALWAYS TREATED WITH A DIURETIC

Edema is not always treated with a diuretic. In a patient who has a pericardial effusion that has developed slowly and who has been drinking enough fluid to keep the central venous pressure higher than the pericardial pressure, a diuretic can remove enough volume from the circulation to lower the central venous pressure below the intrapericardial pressure and thus convert a benign pericardial effusion to potentially lethal cardiac tamponade.

One must understand the cause of edema or low urine output before treating it. This underscores the importance of the history and the physical examination. All of the following must be assessed:

• Symptoms and time course of the illness
• Concurrent medical illnesses
• Neck veins
• Blood pressure and its response to inspiration
• Heart sounds
• Heart rate and rhythm
• Abdominal organ engorgement
• Edema (or its absence).

PEARL 3: UNDERSTANDING THE CAUSE IS ESSENTIAL

Understanding the cause of cardiac tamponade is essential.

A trauma patient first encountered in the emergency department may have an underlying disease, but the focus is squarely on the effects of trauma or violent injury. In a patient with multiple trauma, hypotension and tachycardia that do not respond to intravenous volume replacement when there is an obvious rise in central venous pressure should be clues to cardiac tamponade.¹

If the patient has recently undergone a cardiac procedure (for example, cardiac surgery, myocardial biopsy, coronary intervention, electrophysiologic study with intracardiac electrodes, transvenous pacemaker placement, pacemaker lead extraction, or radiofrequency ablation), knowing about the procedure narrows the differential diagnosis when hypotension, tachycardia, and jugular venous distention develop.

PEARL 4: CARDIAC OR AORTIC RUPTURE REQUIRES SURGERY

When the etiology of cardiac tamponade is cardiac or aortic rupture, the treatment is surgical.

Painful sudden causes of cardiac tamponade include hemopericardium due to rupture of the free wall after myocardial infarction, and spontaneous or posttraumatic dissection and rupture of the ascending aorta. Prompt diagnosis is necessary, but since these lesions will not close and heal spontaneously, the definitive treatment should be surgery. Moreover, needle removal of intrapericardial blood that has been opposing further bleeding is sure to permit bleeding to recur, often with lethal consequences.²

Causes of cardiac tamponade that have a less-acute onset are likely to be complications of medical problems. Medical illnesses known to be associated with cardiac tamponade include:

• Infectious disease (idiopathic or viral, associated with smallpox vaccination, mycobacterial, purulent bacterial, fungal)
• Metastatic cancer (lung, breast, esophagus, lymphoma, pancreas, liver, leukemia, stomach, melanoma)³
• Connective tissue disease (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, Wegener granulomatosis, acute rheumatic fever)
• Endocrine disease (hypothyroidism)
• Drug side effects (procainamide, isoniazid, hydralazine, minoxidil, phenytoin, anticoagulants, methysergide)
• Inflammatory bowel disease (Crohn disease, ulcerative colitis)
• Congestive heart failure
• Uremia
• Radiation therapy
• Postmyocardial infarction syndrome (Dressler syndrome)
• Postpericardiotomy syndrome.

PEARL 5: REVIEW IMAGING BEFORE DIAGNOSING

What often brings a patient with cardiac tamponade to the attention of the physician is a finding on echocardiography, computed tomography, or magnetic resonance imaging of the chest.

Always review the imaging studies before making the diagnosis of cardiac tamponade. These tests must be reviewed to assess the anatomy and the size and location of the effusion. Particularly, one must look for atrial and right ventricular collapse and inferior vena caval plethora, which are echocardiographic signs of cardiac tamponade.⁴ Figures 1, 2, and 3 show imaging studies in a patient who presented with worsening cough 2 weeks after undergoing a cardiac procedure and who was found to have cardiac tamponade.

When the history and these imaging studies place cardiac tamponade high in the differential diagnosis as the cause of edema or dyspnea, it is time to reexamine the patient. The best first step is to measure pulsus paradoxus.

HOW PULSUS PARADOXUS OCCURS

To fully appreciate the subtleties of the next pearls, it is necessary to understand the pathophysiology of cardiac tamponade.

When pericardial fluid accumulation raises the pericardial pressure above the central venous pressure and pulmonary venous pressure (intravascular pressure), blood will not passively return to the right side of the heart from the venae cavae nor to the left side of the heart from the pulmonary veins unless it is influenced by the effects of respiration on intrathoracic pressure. During respiration, the right and left sides of the heart are alternately filled and deprived of their respective venous return.

During inspiration, as the intrathoracic pressure decreases, blood in the venae cavae empties into the right side of the heart, while blood in the pulmonary veins preferentially remains in the pulmonary veins, underfilling the left side of the heart. Since the right ventricle is more filled than the left ventricle during inspiration, the ventricular septum shifts from right to left, further opposing pulmonary venous return. As a result, during cardiac tamponade, the systemic blood pressure falls with inspiration.

During expiration the opposite occurs. Expiration decreases the intrathoracic volume, so the intrathoracic pressure rises. This tends to oppose vena caval return to the right side of the heart and to favor pulmonary venous return to the left side of the heart. The ventricular septum shifts from left to right, further accommodating left ventricular filling, raising stroke volume, and increasing blood pressure. This exaggerated alternate filling of the right and left sides of the heart during cardiac tamponade is what accounts for pulsus paradoxus, an inspiratory fall in systolic blood pressure of greater than 10 mm Hg.

If intravascular pressure is low (due to hemorrhage, dehydration, or diuretic therapy), the pressure in the pericardial space needed to oppose venous return is much less. In this low-pressure scenario, the results are low cardiac output and hypotension, which are treated by giving intravenous fluids to maintain intravascular volume.

PEARL 6: MEASURE PULSUS PARADOXUS

When cardiac tamponade is considered, one must always measure the pulsus paradoxus.

The term pulsus paradoxus was coined by Adolph Kussmaul in 1873, before physicians could even measure blood pressure. All they could do at that time was palpate the pulse and listen to the heart. Kussmaul described his observation as a conspicuous discrepancy between the cardiac action and the arterial pulse.

Although not described by Kussmaul, another explanation for this finding might be more suited to the use of the word “paradoxical.” When the pulse is palpated in a normal patient, with inspiration the pulse rate will increase via the Bainbridge reflex, and with expiration it will decrease. But in a patient with cardiac tamponade, there is a paradoxical inspiratory slowing of the pulse (because the decreased magnitude of the pulse at times makes it imperceptible) and an expiratory increase in pulse rate as the magnitude of the pulse again makes it palpable.

The magnitude of the fall in systolic blood pressure during inspiration has been used to estimate the level of hemodynamic impairment resulting from pericardial effusion.⁵ A rapidly accumulating pericardial effusion can have more hemodynamic impact than a much larger one that accumulates slowly. Thus, the intrapericardial pressure must be considered more than the volume of pericardial fluid.

When there is severe cardiac tamponade and overt pulsus paradoxus, simple palpation of a proximal arterial pulse can detect a marked inspiratory decrease or loss of the pulse, which returns with expiration. Tachycardia is almost always present, unless the cause is hypothyroidism.⁶

How to measure pulsus paradoxus with a manual sphygmomanometer

A stethoscope and manual sphygmomanometer are all that is needed to measure pulsus paradoxus. A noninvasive blood pressure monitor that averages multiple measurements cannot detect or quantify pulsus paradoxus.

The patient should be supine with the head elevated 30° to 45°, and the examiner should be seated comfortably at the patient’s side. The manometer should be on the opposite side of the patient in plain view of the examiner. Position the cuff on the arm above the elbow and place your stethoscope on the antecubital fossa. Then:

• Inflate the cuff 20 mm Hg above the highest systolic pressure previously auscultated.
• Slowly decrease the manometer pressure by 5 mm Hg and hold it there through two or three respiratory cycles while listening for the first Korotkoff (systolic) sound. Repeat this until you can hear the systolic sound (but only during expiration) and mentally note the pressure.
• Continue to decrease the manometer pressure by 5-mm Hg increments while listening. When the Korotkoff sounds no longer disappear with inspiration, mentally note this second value as well. The pulsus paradoxus is the difference between these values.
• When the Korotkoff sounds disappear as the manometer pressure is decreased, note this final value. This is the diastolic blood pressure.

PEARL 7: THE PLETHYSMOGRAM WAVE-FORM PARALLELS PULSUS PARADOXUS

Manual measurement of blood pressure and pulsus paradoxus can be difficult, especially in an obese patient or one with a fat-distorted arm on which the cuff does not maintain its position. In such patients, increased girth of the neck and abdomen also make it difficult to assess the jugular venous distention and visceral organ engorgement that characterize cardiac tamponade.

When the use of a sphygmomanometer is not possible, an arterial catheter can be inserted to demonstrate pulsus paradoxus. Simpler, however, is the novel use of another noninvasive instrument to detect and coarsely quantify pulsus paradoxus.⁷ The waveform on finger pulse oximetry can demonstrate pulsus paradoxus. The plethysmogram of the finger pulse oximeter can demonstrate the decrease in magnitude of the waveform with each inspiration (Figure 4).

Caution must be taken when interpreting this waveform, as with any measurement of pulsus paradoxus, to exclude a concomitant arrhythmia.

PEARL 8: PULSUS PARADOXUS WITHOUT CARDIAC TAMPONADE

Pulsus paradoxus can be present in the absence of cardiac tamponade. Once pulsus paradoxus of more than 10 mm Hg is measured, one must be sure the patient does not have a condition that can cause pulsus paradoxus without cardiac tamponade. Most of these are pulmonary conditions that necessitate an exaggerated inspiratory effort that can lower intrathoracic pressure sufficiently to oppose pulmonary venous return and cause a fall in systemic blood pressure:

• Chronic bronchitis
• Emphysema
• Mucus plug
• Pneumothorax
• Pulmonary embolism
• Stridor.

In these, there may be pulsus paradoxus, but not due to cardiac tamponade.

PEARL 9: CARDIAC TAMPONADE CAN BE PRESENT WITHOUT PULSUS PARADOXUS

Cardiac tamponade can be present without pulsus paradoxus. This occurs when certain conditions prevent inspiratory underfilling of the left ventricle relative to the filling of the right ventricle.⁸

How does this work? In cardiac tamponade, factors that drive the exaggerated fall in arterial pressure with inspiration (pulsus paradoxus) are the augmented right ventricular filling and the decreased left ventricular filling, both due to the lowering of the intrathoracic pressure. As the vena caval emptying is augmented, the right ventricular filling is increased, the ventricular septum shifts to the left, and pulmonary venous return to the heart is decreased.

Factors that can oppose pulsus paradoxus:

• Positive pressure ventilation prevents pulsus paradoxus by preventing the fall in intrathoracic pressure.
• Severe aortic regurgitation does not permit underfilling of the left ventricle during inspiration.
• An atrial septal defect will always equalize the right and left atrial pressures, preventing differential right ventricular and left ventricular filling with inspiration.
• Severe left ventricular hypertrophy does not permit the inspiratory shift of the ventricular septum from right to left that would otherwise lead to decreased left ventricular filling.
• Severe left ventricular dysfunction, with its low stroke volume and severe elevation of left ventricular end-diastolic pressure, never permits underfilling of the left ventricle, despite cardiac tamponade and an inspiratory decrease in intrathoracic pressure.
• Intravascular volume depletion due to hemorrhage, hemodialysis, or mistaken use of diuretics to treat edema can cause marked hypotension, making pulsus paradoxus impossible to detect.

Knowledge of underlying medical conditions, the likelihood of their causing cardiac tamponade, and the appearance of the echocardiogram prompt the physician to look further when the presence or absence of pulsus paradoxus does not fit with the working diagnosis.

The echocardiogram can give hints to the etiology of a pericardial effusion, such as clotted blood after trauma or a cardiac-perforating procedure, tumor studding of the epicardium,⁹ or fibrin strands indicating chronicity or an inflammatory process.¹⁰ Diastolic collapse of the right ventricle, more than collapse of the right atrium or left atrium, speaks for the severity of cardiac tamponade. With hemodynamically significant pericardial effusion and cardiac tamponade, the inferior vena cava is distended and does not decrease in size with inspiration unless there is severe intravascular volume depletion, at which time the inferior vena cava is underfilled throughout the respiratory cycle.

PEARL 10: PLAN HOW TO DRAIN

The size and location of the pericardial effusion and the patient’s hemodynamics must be integrated when deciding how to relieve cardiac tamponade. When cardiac tamponade is indeed severe and the patient and physician agree that it must be drained, the options are percutaneous needle aspiration (pericardiocentesis) and surgical pericardiostomy (creation of a pericardial window). Here again, as assessed by echocardiography, the access to the pericardial fluid should influence the choice.

Pericardiocentesis can be safely done if certain criteria are met. The patient must be able to lie still in the supine position, perhaps with the head of the bed elevated 30 degrees. Anticoagulation must be reversed or allowed time to resolve if drainage is not an emergency.

Pericardiocentesis can be risky or unsuccessful if there is not enough pericardial fluid to permit respiratory cardiac motion without perforating the heart with the needle; if the effusion is loculated (confined to a pocket) posteriorly; or if it is too far from the skin to permit precise control and placement of a spinal needle into the pericardial space. In cases of cardiac tamponade in which the anatomy indicates surgical pericardiostomy but severe hypotension prevents the induction of anesthesia and positive-pressure ventilation—which can result in profound, irreversible hypotension—percutaneous needle drainage (pericardiocentesis) should be performed in the operating room to relieve the tamponade before the induction of anesthesia and the surgical drainage.¹¹

To reiterate, a suspected cardiac or aortic rupture that causes cardiac tamponade is usually large and not apt to self-seal. In such cases, the halt in the accumulation of pericardial blood is due to hypotension and not due to spontaneous resolution. Open surgical drainage is required from the outset because an initial success of pericardiocentesis yields to the recurrence of cardiac tamponade.

PEARL 11: ANTICIPATE WHAT THE FLUID SHOULD LOOK LIKE

Before performing pericardiocentesis, anticipate the appearance of the pericardial fluid on the basis of the presumed etiology, ie:

• Sanguinous—trauma, heart surgery, cardiac perforation from a procedure, anticoagulation, uremia, or malignancy
• Serous—congestive heart failure, acute radiation therapy
• Purulent—infections (natural or postoperative)
• Turbid (like gold paint)—mycobacterial infection, rheumatoid arthritis, myxedema
• Chylous—pericardium fistulized to the thoracic duct by a natural or postsurgical cause.

Sanguinous pericardial effusion encountered during a pericardiocentesis, if not anticipated, can be daunting and can cause the operator to question if it is the result of inadvertent needle placement in a cardiac chamber. If the needle is indeed in the heart, blood often surges out under pressure in pulses, which strongly suggests that the needle is not in the pericardial space and should be removed; but if confirmation of the location is needed before removing the needle, it can be done by injecting 2 mL of agitated sterile saline through the pericardiocentesis needle during echocardiographic imaging.¹²

Before inserting the needle, the ideal access location and needle angle must be determined by the operator with echocardiographic transducer in hand. The distance from skin to a point just through the parietal pericardium can also be measured at this time.

Once the needle is in the pericardial fluid (and you are confident of its placement), removal of 50 to 100 mL of the fluid with a large syringe can be enough to afford the patient easier breathing, higher blood pressure, and lower pulsus paradoxus—and even the physician will breathe easier. The same syringe can be filled and emptied multiple times. Less traumatic and more complete removal of pericardial fluid requires insertion of a multihole pigtail catheter over a J-tipped guidewire that is introduced through the needle.

PEARL 12: DRAIN SLOWLY TO AVOID PULMONARY EDEMA

Pulmonary edema is an uncommon complication of pericardiocentesis that might be avoidable. Heralded by sudden coughing and pink, frothy sputum, it can rapidly deteriorate into respiratory failure. The mechanism has been attributed to a sudden increase in right ventricular stroke volume and resultant left ventricular filling after the excess pericardial fluid has been removed, before the systemic arteries, which constrict to keep the systemic blood pressure up during cardiac tamponade, have had time to relax.¹³

To avoid this complication, if the volume of pericardial fluid responsible for cardiac tamponade is large, it should be removed slowly,¹⁴ stopping for a several-minute rest after each 250 mL. Catheter removal of pericardial fluid by gravity drainage over 24 hours has been suggested.¹⁵ A drawback to this approach is catheter clotting or sludging before all the fluid has been removed. It is helpful to keep the drainage catheter close to the patient’s body temperature to make the fluid less viscous. Output should be monitored hourly.

When the pericardial fluid has been completely drained, one must decide how long to leave the catheter in. One reason to remove the catheter at this time is that it causes pleuritic pain; another is to avoid introducing infection. A reason to leave the catheter in is to observe the effect of medical treatment on the hourly pericardial fluid output. Nonsteroidal anti-inflammatory drugs are the drugs of first choice when treating pericardial inflammation and suppressing production of pericardial fluid.¹⁶ In most cases the catheter should not be left in place for more than 3 days.

Laboratory analysis of the pericardial fluid should shed light on its suspected cause. Analysis usually involves chemistry testing, microscopic inspection of blood cell smears, cytology, microbiologic stains and cultures, and immunologic tests. Results often take days. Meyers and colleagues¹⁷ expound on this subject.

Cardiac tamponade is a life-threatening condition that can be palliated or cured, depending on its cause and on the timeliness of treatment. Making a timely diagnosis and providing the appropriate treatment can be gratifying for both patient and physician.

Cardiac tamponade occurs when fluid in the pericardial space reaches a pressure exceeding central venous pressure. This leads to jugular venous distention, visceral organ engorgement, edema, and elevated pulmonary venous pressure that causes dyspnea. Despite compensatory tachycardia, the decrease in cardiac filling leads to a fall in cardiac output and to arterial hypoperfusion of vital organs.

PEARL 1: SLOW ACCUMULATION LEADS TO EDEMA

The rate at which pericardial fluid accumulates influences the clinical presentation of cardiac tamponade, in particular whether or not there is edema. Whereas rapid accumulation is characterized more by hypotension than by edema, the slow accumulation of pericardial fluid affords the patient time to drink enough liquid to keep the central venous pressure higher than the rising pericardial pressure. Thus, edema and dyspnea are more prominent features of cardiac tamponade when there is a slow rise in pericardial pressure.

PEARL 2: EDEMA IS NOT ALWAYS TREATED WITH A DIURETIC

Edema is not always treated with a diuretic. In a patient who has a pericardial effusion that has developed slowly and who has been drinking enough fluid to keep the central venous pressure higher than the pericardial pressure, a diuretic can remove enough volume from the circulation to lower the central venous pressure below the intrapericardial pressure and thus convert a benign pericardial effusion to potentially lethal cardiac tamponade.

One must understand the cause of edema or low urine output before treating it. This underscores the importance of the history and the physical examination. All of the following must be assessed:

• Symptoms and time course of the illness
• Concurrent medical illnesses
• Neck veins
• Blood pressure and its response to inspiration
• Heart sounds
• Heart rate and rhythm
• Abdominal organ engorgement
• Edema (or its absence).

PEARL 3: UNDERSTANDING THE CAUSE IS ESSENTIAL

Understanding the cause of cardiac tamponade is essential.

A trauma patient first encountered in the emergency department may have an underlying disease, but the focus is squarely on the effects of trauma or violent injury. In a patient with multiple trauma, hypotension and tachycardia that do not respond to intravenous volume replacement when there is an obvious rise in central venous pressure should be clues to cardiac tamponade.¹

If the patient has recently undergone a cardiac procedure (for example, cardiac surgery, myocardial biopsy, coronary intervention, electrophysiologic study with intracardiac electrodes, transvenous pacemaker placement, pacemaker lead extraction, or radiofrequency ablation), knowing about the procedure narrows the differential diagnosis when hypotension, tachycardia, and jugular venous distention develop.

PEARL 4: CARDIAC OR AORTIC RUPTURE REQUIRES SURGERY

When the etiology of cardiac tamponade is cardiac or aortic rupture, the treatment is surgical.

Painful sudden causes of cardiac tamponade include hemopericardium due to rupture of the free wall after myocardial infarction, and spontaneous or posttraumatic dissection and rupture of the ascending aorta. Prompt diagnosis is necessary, but since these lesions will not close and heal spontaneously, the definitive treatment should be surgery. Moreover, needle removal of intrapericardial blood that has been opposing further bleeding is sure to permit bleeding to recur, often with lethal consequences.²

Causes of cardiac tamponade that have a less-acute onset are likely to be complications of medical problems. Medical illnesses known to be associated with cardiac tamponade include:

• Infectious disease (idiopathic or viral, associated with smallpox vaccination, mycobacterial, purulent bacterial, fungal)
• Metastatic cancer (lung, breast, esophagus, lymphoma, pancreas, liver, leukemia, stomach, melanoma)³
• Connective tissue disease (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, Wegener granulomatosis, acute rheumatic fever)
• Endocrine disease (hypothyroidism)
• Drug side effects (procainamide, isoniazid, hydralazine, minoxidil, phenytoin, anticoagulants, methysergide)
• Inflammatory bowel disease (Crohn disease, ulcerative colitis)
• Congestive heart failure
• Uremia
• Radiation therapy
• Postmyocardial infarction syndrome (Dressler syndrome)
• Postpericardiotomy syndrome.

PEARL 5: REVIEW IMAGING BEFORE DIAGNOSING

What often brings a patient with cardiac tamponade to the attention of the physician is a finding on echocardiography, computed tomography, or magnetic resonance imaging of the chest.

Always review the imaging studies before making the diagnosis of cardiac tamponade. These tests must be reviewed to assess the anatomy and the size and location of the effusion. Particularly, one must look for atrial and right ventricular collapse and inferior vena caval plethora, which are echocardiographic signs of cardiac tamponade.⁴ Figures 1, 2, and 3 show imaging studies in a patient who presented with worsening cough 2 weeks after undergoing a cardiac procedure and who was found to have cardiac tamponade.

When the history and these imaging studies place cardiac tamponade high in the differential diagnosis as the cause of edema or dyspnea, it is time to reexamine the patient. The best first step is to measure pulsus paradoxus.

HOW PULSUS PARADOXUS OCCURS

To fully appreciate the subtleties of the next pearls, it is necessary to understand the pathophysiology of cardiac tamponade.

When pericardial fluid accumulation raises the pericardial pressure above the central venous pressure and pulmonary venous pressure (intravascular pressure), blood will not passively return to the right side of the heart from the venae cavae nor to the left side of the heart from the pulmonary veins unless it is influenced by the effects of respiration on intrathoracic pressure. During respiration, the right and left sides of the heart are alternately filled and deprived of their respective venous return.

During inspiration, as the intrathoracic pressure decreases, blood in the venae cavae empties into the right side of the heart, while blood in the pulmonary veins preferentially remains in the pulmonary veins, underfilling the left side of the heart. Since the right ventricle is more filled than the left ventricle during inspiration, the ventricular septum shifts from right to left, further opposing pulmonary venous return. As a result, during cardiac tamponade, the systemic blood pressure falls with inspiration.

During expiration the opposite occurs. Expiration decreases the intrathoracic volume, so the intrathoracic pressure rises. This tends to oppose vena caval return to the right side of the heart and to favor pulmonary venous return to the left side of the heart. The ventricular septum shifts from left to right, further accommodating left ventricular filling, raising stroke volume, and increasing blood pressure. This exaggerated alternate filling of the right and left sides of the heart during cardiac tamponade is what accounts for pulsus paradoxus, an inspiratory fall in systolic blood pressure of greater than 10 mm Hg.

If intravascular pressure is low (due to hemorrhage, dehydration, or diuretic therapy), the pressure in the pericardial space needed to oppose venous return is much less. In this low-pressure scenario, the results are low cardiac output and hypotension, which are treated by giving intravenous fluids to maintain intravascular volume.

PEARL 6: MEASURE PULSUS PARADOXUS

When cardiac tamponade is considered, one must always measure the pulsus paradoxus.

The term pulsus paradoxus was coined by Adolph Kussmaul in 1873, before physicians could even measure blood pressure. All they could do at that time was palpate the pulse and listen to the heart. Kussmaul described his observation as a conspicuous discrepancy between the cardiac action and the arterial pulse.

Although not described by Kussmaul, another explanation for this finding might be more suited to the use of the word “paradoxical.” When the pulse is palpated in a normal patient, with inspiration the pulse rate will increase via the Bainbridge reflex, and with expiration it will decrease. But in a patient with cardiac tamponade, there is a paradoxical inspiratory slowing of the pulse (because the decreased magnitude of the pulse at times makes it imperceptible) and an expiratory increase in pulse rate as the magnitude of the pulse again makes it palpable.

The magnitude of the fall in systolic blood pressure during inspiration has been used to estimate the level of hemodynamic impairment resulting from pericardial effusion.⁵ A rapidly accumulating pericardial effusion can have more hemodynamic impact than a much larger one that accumulates slowly. Thus, the intrapericardial pressure must be considered more than the volume of pericardial fluid.

When there is severe cardiac tamponade and overt pulsus paradoxus, simple palpation of a proximal arterial pulse can detect a marked inspiratory decrease or loss of the pulse, which returns with expiration. Tachycardia is almost always present, unless the cause is hypothyroidism.⁶

How to measure pulsus paradoxus with a manual sphygmomanometer

A stethoscope and manual sphygmomanometer are all that is needed to measure pulsus paradoxus. A noninvasive blood pressure monitor that averages multiple measurements cannot detect or quantify pulsus paradoxus.

The patient should be supine with the head elevated 30° to 45°, and the examiner should be seated comfortably at the patient’s side. The manometer should be on the opposite side of the patient in plain view of the examiner. Position the cuff on the arm above the elbow and place your stethoscope on the antecubital fossa. Then:

• Inflate the cuff 20 mm Hg above the highest systolic pressure previously auscultated.
• Slowly decrease the manometer pressure by 5 mm Hg and hold it there through two or three respiratory cycles while listening for the first Korotkoff (systolic) sound. Repeat this until you can hear the systolic sound (but only during expiration) and mentally note the pressure.
• Continue to decrease the manometer pressure by 5-mm Hg increments while listening. When the Korotkoff sounds no longer disappear with inspiration, mentally note this second value as well. The pulsus paradoxus is the difference between these values.
• When the Korotkoff sounds disappear as the manometer pressure is decreased, note this final value. This is the diastolic blood pressure.

PEARL 7: THE PLETHYSMOGRAM WAVE-FORM PARALLELS PULSUS PARADOXUS

Manual measurement of blood pressure and pulsus paradoxus can be difficult, especially in an obese patient or one with a fat-distorted arm on which the cuff does not maintain its position. In such patients, increased girth of the neck and abdomen also make it difficult to assess the jugular venous distention and visceral organ engorgement that characterize cardiac tamponade.

When the use of a sphygmomanometer is not possible, an arterial catheter can be inserted to demonstrate pulsus paradoxus. Simpler, however, is the novel use of another noninvasive instrument to detect and coarsely quantify pulsus paradoxus.⁷ The waveform on finger pulse oximetry can demonstrate pulsus paradoxus. The plethysmogram of the finger pulse oximeter can demonstrate the decrease in magnitude of the waveform with each inspiration (Figure 4).

Caution must be taken when interpreting this waveform, as with any measurement of pulsus paradoxus, to exclude a concomitant arrhythmia.

PEARL 8: PULSUS PARADOXUS WITHOUT CARDIAC TAMPONADE

Pulsus paradoxus can be present in the absence of cardiac tamponade. Once pulsus paradoxus of more than 10 mm Hg is measured, one must be sure the patient does not have a condition that can cause pulsus paradoxus without cardiac tamponade. Most of these are pulmonary conditions that necessitate an exaggerated inspiratory effort that can lower intrathoracic pressure sufficiently to oppose pulmonary venous return and cause a fall in systemic blood pressure:

• Chronic bronchitis
• Emphysema
• Mucus plug
• Pneumothorax
• Pulmonary embolism
• Stridor.

In these, there may be pulsus paradoxus, but not due to cardiac tamponade.

PEARL 9: CARDIAC TAMPONADE CAN BE PRESENT WITHOUT PULSUS PARADOXUS

Cardiac tamponade can be present without pulsus paradoxus. This occurs when certain conditions prevent inspiratory underfilling of the left ventricle relative to the filling of the right ventricle.⁸

How does this work? In cardiac tamponade, factors that drive the exaggerated fall in arterial pressure with inspiration (pulsus paradoxus) are the augmented right ventricular filling and the decreased left ventricular filling, both due to the lowering of the intrathoracic pressure. As the vena caval emptying is augmented, the right ventricular filling is increased, the ventricular septum shifts to the left, and pulmonary venous return to the heart is decreased.

Factors that can oppose pulsus paradoxus:

• Positive pressure ventilation prevents pulsus paradoxus by preventing the fall in intrathoracic pressure.
• Severe aortic regurgitation does not permit underfilling of the left ventricle during inspiration.
• An atrial septal defect will always equalize the right and left atrial pressures, preventing differential right ventricular and left ventricular filling with inspiration.
• Severe left ventricular hypertrophy does not permit the inspiratory shift of the ventricular septum from right to left that would otherwise lead to decreased left ventricular filling.
• Severe left ventricular dysfunction, with its low stroke volume and severe elevation of left ventricular end-diastolic pressure, never permits underfilling of the left ventricle, despite cardiac tamponade and an inspiratory decrease in intrathoracic pressure.
• Intravascular volume depletion due to hemorrhage, hemodialysis, or mistaken use of diuretics to treat edema can cause marked hypotension, making pulsus paradoxus impossible to detect.

Knowledge of underlying medical conditions, the likelihood of their causing cardiac tamponade, and the appearance of the echocardiogram prompt the physician to look further when the presence or absence of pulsus paradoxus does not fit with the working diagnosis.

The echocardiogram can give hints to the etiology of a pericardial effusion, such as clotted blood after trauma or a cardiac-perforating procedure, tumor studding of the epicardium,⁹ or fibrin strands indicating chronicity or an inflammatory process.¹⁰ Diastolic collapse of the right ventricle, more than collapse of the right atrium or left atrium, speaks for the severity of cardiac tamponade. With hemodynamically significant pericardial effusion and cardiac tamponade, the inferior vena cava is distended and does not decrease in size with inspiration unless there is severe intravascular volume depletion, at which time the inferior vena cava is underfilled throughout the respiratory cycle.

PEARL 10: PLAN HOW TO DRAIN

The size and location of the pericardial effusion and the patient’s hemodynamics must be integrated when deciding how to relieve cardiac tamponade. When cardiac tamponade is indeed severe and the patient and physician agree that it must be drained, the options are percutaneous needle aspiration (pericardiocentesis) and surgical pericardiostomy (creation of a pericardial window). Here again, as assessed by echocardiography, the access to the pericardial fluid should influence the choice.

Pericardiocentesis can be safely done if certain criteria are met. The patient must be able to lie still in the supine position, perhaps with the head of the bed elevated 30 degrees. Anticoagulation must be reversed or allowed time to resolve if drainage is not an emergency.

Pericardiocentesis can be risky or unsuccessful if there is not enough pericardial fluid to permit respiratory cardiac motion without perforating the heart with the needle; if the effusion is loculated (confined to a pocket) posteriorly; or if it is too far from the skin to permit precise control and placement of a spinal needle into the pericardial space. In cases of cardiac tamponade in which the anatomy indicates surgical pericardiostomy but severe hypotension prevents the induction of anesthesia and positive-pressure ventilation—which can result in profound, irreversible hypotension—percutaneous needle drainage (pericardiocentesis) should be performed in the operating room to relieve the tamponade before the induction of anesthesia and the surgical drainage.¹¹

To reiterate, a suspected cardiac or aortic rupture that causes cardiac tamponade is usually large and not apt to self-seal. In such cases, the halt in the accumulation of pericardial blood is due to hypotension and not due to spontaneous resolution. Open surgical drainage is required from the outset because an initial success of pericardiocentesis yields to the recurrence of cardiac tamponade.

PEARL 11: ANTICIPATE WHAT THE FLUID SHOULD LOOK LIKE

Before performing pericardiocentesis, anticipate the appearance of the pericardial fluid on the basis of the presumed etiology, ie:

• Sanguinous—trauma, heart surgery, cardiac perforation from a procedure, anticoagulation, uremia, or malignancy
• Serous—congestive heart failure, acute radiation therapy
• Purulent—infections (natural or postoperative)
• Turbid (like gold paint)—mycobacterial infection, rheumatoid arthritis, myxedema
• Chylous—pericardium fistulized to the thoracic duct by a natural or postsurgical cause.

Sanguinous pericardial effusion encountered during a pericardiocentesis, if not anticipated, can be daunting and can cause the operator to question if it is the result of inadvertent needle placement in a cardiac chamber. If the needle is indeed in the heart, blood often surges out under pressure in pulses, which strongly suggests that the needle is not in the pericardial space and should be removed; but if confirmation of the location is needed before removing the needle, it can be done by injecting 2 mL of agitated sterile saline through the pericardiocentesis needle during echocardiographic imaging.¹²

Before inserting the needle, the ideal access location and needle angle must be determined by the operator with echocardiographic transducer in hand. The distance from skin to a point just through the parietal pericardium can also be measured at this time.

Once the needle is in the pericardial fluid (and you are confident of its placement), removal of 50 to 100 mL of the fluid with a large syringe can be enough to afford the patient easier breathing, higher blood pressure, and lower pulsus paradoxus—and even the physician will breathe easier. The same syringe can be filled and emptied multiple times. Less traumatic and more complete removal of pericardial fluid requires insertion of a multihole pigtail catheter over a J-tipped guidewire that is introduced through the needle.

PEARL 12: DRAIN SLOWLY TO AVOID PULMONARY EDEMA

Pulmonary edema is an uncommon complication of pericardiocentesis that might be avoidable. Heralded by sudden coughing and pink, frothy sputum, it can rapidly deteriorate into respiratory failure. The mechanism has been attributed to a sudden increase in right ventricular stroke volume and resultant left ventricular filling after the excess pericardial fluid has been removed, before the systemic arteries, which constrict to keep the systemic blood pressure up during cardiac tamponade, have had time to relax.¹³

To avoid this complication, if the volume of pericardial fluid responsible for cardiac tamponade is large, it should be removed slowly,¹⁴ stopping for a several-minute rest after each 250 mL. Catheter removal of pericardial fluid by gravity drainage over 24 hours has been suggested.¹⁵ A drawback to this approach is catheter clotting or sludging before all the fluid has been removed. It is helpful to keep the drainage catheter close to the patient’s body temperature to make the fluid less viscous. Output should be monitored hourly.

When the pericardial fluid has been completely drained, one must decide how long to leave the catheter in. One reason to remove the catheter at this time is that it causes pleuritic pain; another is to avoid introducing infection. A reason to leave the catheter in is to observe the effect of medical treatment on the hourly pericardial fluid output. Nonsteroidal anti-inflammatory drugs are the drugs of first choice when treating pericardial inflammation and suppressing production of pericardial fluid.¹⁶ In most cases the catheter should not be left in place for more than 3 days.

Laboratory analysis of the pericardial fluid should shed light on its suspected cause. Analysis usually involves chemistry testing, microscopic inspection of blood cell smears, cytology, microbiologic stains and cultures, and immunologic tests. Results often take days. Meyers and colleagues¹⁷ expound on this subject.

Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.

The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).

Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.

In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.¹ Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.¹ Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).²

CLINICAL FEATURES

Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.^3,4

ELECTROCARDIOGRAPHIC FEATURES

The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):

Short or absent ST segment

This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.⁵

Tall and peaked T wave

A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.⁵

QT response to heart rate

Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.^6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.

BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?

In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:

Corrected QT (QTc) = [QT interval/square root of the RR interval]

Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.^8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.⁸ Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.¹²

Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.¹³ The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.^14,15

ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME

Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.

Differential diagnosis of short QT interval

In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.

• Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex¹⁶
• Hyperkalemia¹⁷
• Acidosis¹⁷
• Increased vagal tone¹⁷
• After ventricular fibrillation (thought to be related to increased intracellular calcium)¹⁸
• Digitalis use¹⁹
• Androgen use.²⁰

Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.²¹

Which interval to use: QT or QTc?

Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.^8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.¹⁶

In a review of cases of short QT syndrome worldwide, Bjerregaard et al²² found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.

Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.^16,22

To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.²² In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.¹⁶

Recently, Gollob et al²³ proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).

For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.

Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.

THE SCOPE OF THE DISEASE

In a recent review of the literature, Gollob et al²³ found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.

Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.^14,15

MUTATIONS IN CARDIAC ION CHANNELS

Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).

The cardiac action potential

To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.²⁴ In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).

In phase 0, the cardiac cell rapidly depolarizes.

Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:

• The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
• The relative refractory period: the cell can respond to a stimulus that is stronger than normal
• The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.

In phase 4, the cell is completely repolarized, and the cycle can start again.

Short QT syndrome 1. In 2004, Brugada et al²⁵ identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.

Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.^26,27

Short QT syndromes 4 and 5 were identified by Antzelevitch et al,²⁸ who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.²⁸

MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME

The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.

It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).²⁹

WHEN TO THINK OF SHORT QT SYNDROME

In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.⁴

TREATMENT AND PROGNOSIS

Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.

Implantable cardioverter-defibrillators

Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.³⁰ In addition, some patients may not want an ICD or may even not qualify for this therapy.

A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.³¹

For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.

Antiarrhythmic drugs

Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al³² studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.

In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al³³ noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.

RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES

The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.

Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.

The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).

Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.

In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.¹ Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.¹ Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).²

CLINICAL FEATURES

Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.^3,4

ELECTROCARDIOGRAPHIC FEATURES

The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):

Short or absent ST segment

This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.⁵

Tall and peaked T wave

A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.⁵

QT response to heart rate

Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.^6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.

BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?

In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:

Corrected QT (QTc) = [QT interval/square root of the RR interval]

Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.^8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.⁸ Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.¹²

Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.¹³ The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.^14,15

ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME

Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.

Differential diagnosis of short QT interval

In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.

• Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex¹⁶
• Hyperkalemia¹⁷
• Acidosis¹⁷
• Increased vagal tone¹⁷
• After ventricular fibrillation (thought to be related to increased intracellular calcium)¹⁸
• Digitalis use¹⁹
• Androgen use.²⁰

Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.²¹

Which interval to use: QT or QTc?

Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.^8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.¹⁶

In a review of cases of short QT syndrome worldwide, Bjerregaard et al²² found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.

Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.^16,22

To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.²² In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.¹⁶

Recently, Gollob et al²³ proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).

For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.

Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.

THE SCOPE OF THE DISEASE

In a recent review of the literature, Gollob et al²³ found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.

Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.^14,15

MUTATIONS IN CARDIAC ION CHANNELS

Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).

The cardiac action potential

To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.²⁴ In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).

In phase 0, the cardiac cell rapidly depolarizes.

Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:

• The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
• The relative refractory period: the cell can respond to a stimulus that is stronger than normal
• The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.

In phase 4, the cell is completely repolarized, and the cycle can start again.

Short QT syndrome 1. In 2004, Brugada et al²⁵ identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.

Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.^26,27

Short QT syndromes 4 and 5 were identified by Antzelevitch et al,²⁸ who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.²⁸

MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME

The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.

It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).²⁹

WHEN TO THINK OF SHORT QT SYNDROME

In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.⁴

TREATMENT AND PROGNOSIS

Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.

Implantable cardioverter-defibrillators

Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.³⁰ In addition, some patients may not want an ICD or may even not qualify for this therapy.

A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.³¹

For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.

Antiarrhythmic drugs

Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al³² studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.

In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al³³ noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.

RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES

The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.

Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.

The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).

Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.

In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.¹ Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.¹ Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).²

CLINICAL FEATURES

Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.^3,4

ELECTROCARDIOGRAPHIC FEATURES

The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):

Short or absent ST segment

This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.⁵

Tall and peaked T wave

A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.⁵

QT response to heart rate

Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.^6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.

BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?

In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:

Corrected QT (QTc) = [QT interval/square root of the RR interval]

Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.^8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.⁸ Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.¹²

Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.¹³ The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.^14,15

ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME

Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.

Differential diagnosis of short QT interval

In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.

• Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex¹⁶
• Hyperkalemia¹⁷
• Acidosis¹⁷
• Increased vagal tone¹⁷
• After ventricular fibrillation (thought to be related to increased intracellular calcium)¹⁸
• Digitalis use¹⁹
• Androgen use.²⁰

Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.²¹

Which interval to use: QT or QTc?

Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.^8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.¹⁶

In a review of cases of short QT syndrome worldwide, Bjerregaard et al²² found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.

Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.^16,22

To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.²² In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.¹⁶

Recently, Gollob et al²³ proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).

For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.

Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.

THE SCOPE OF THE DISEASE

In a recent review of the literature, Gollob et al²³ found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.

Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.^14,15

MUTATIONS IN CARDIAC ION CHANNELS

Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).

The cardiac action potential

To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.²⁴ In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).

In phase 0, the cardiac cell rapidly depolarizes.

Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:

• The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
• The relative refractory period: the cell can respond to a stimulus that is stronger than normal
• The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.

In phase 4, the cell is completely repolarized, and the cycle can start again.

Short QT syndrome 1. In 2004, Brugada et al²⁵ identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.

Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.^26,27

Short QT syndromes 4 and 5 were identified by Antzelevitch et al,²⁸ who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.²⁸

MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME

The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.

It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).²⁹

WHEN TO THINK OF SHORT QT SYNDROME

In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.⁴

TREATMENT AND PROGNOSIS

Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.

Implantable cardioverter-defibrillators

Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.³⁰ In addition, some patients may not want an ICD or may even not qualify for this therapy.

A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.³¹

For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.

Antiarrhythmic drugs

Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al³² studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.

In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al³³ noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.

RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES

The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.

Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.

This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.

THE PREVALENCE OF HEART FAILURE

About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.¹ Patients with systolic heart failure can be classified by degree of severity under two systems:

The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.

The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.²

The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.³

WHICH AMBULATORY PATIENTS ARE MOST AT RISK?

The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.

The European Society of Cardiology⁴ developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:

• Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
• Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
• Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
• Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
• One or more hospitalizations for heart failure in the past 6 months.

Treadmill exercise time is an easily performed test. Hsich et al⁵ found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.

The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,⁶ but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).

Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.

INOTROPIC THERAPY FOR BRIDGING

Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.

Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.⁷

CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES

Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.^8,9 The prognosis is not as good as for combined heart-lung transplantation patients.

Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.

Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.

The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.

Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.

Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.

Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.¹⁰

Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.^11,12 Case 1 (below) is an example of the problem.

Case 1: Poor outcome despite an ideal scenario

A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.

In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.

Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.

The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.

Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.

Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.

Coronary artery vasculopathy is still a major problem

This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.

Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.

THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED

The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.

All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.

In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:

• Local, status 1A
• Local, status 1B
• Zone A, status 1A
• Zone A, status 1B
• Local, status 2
• Zone B, status 1A
• Zone B, status 1B
• Zone A, status 2.

As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.³

The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.¹³ The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.

Heart transplant outcomes are publicly reported

The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.

Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.

MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?

Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.

Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.

Case 2: A good outcome despite a poor prognosis

A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.

Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.

LVADs continue to improve

Many devices are available for mechanical circulatory support.¹⁴ In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.

LVADs are of three types:

• Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
• Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
• Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.

The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.¹⁵ The results of such studies and the increased durability of the devices have led to their rapidly expanded use.

The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.¹⁶ In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.¹⁷

Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).¹⁸ Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.¹⁹ This study can be viewed as supporting the use of LVADs as destination therapy.

Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.²⁰

Adverse events with LVADs have improved, but continue to be of concern

Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.¹⁸

Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.

Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.²¹

Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.

Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.

Good data are kept on device outcomes

The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.

The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.²² The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.²³ An earlier report showed that the level of illness at the time of implantation predicts survival²⁴; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.

The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.

On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.

FUTURE DIRECTIONS

PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.

A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.

Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.

This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.

THE PREVALENCE OF HEART FAILURE

About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.¹ Patients with systolic heart failure can be classified by degree of severity under two systems:

The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.

The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.²

The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.³

WHICH AMBULATORY PATIENTS ARE MOST AT RISK?

The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.

The European Society of Cardiology⁴ developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:

• Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
• Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
• Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
• Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
• One or more hospitalizations for heart failure in the past 6 months.

Treadmill exercise time is an easily performed test. Hsich et al⁵ found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.

The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,⁶ but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).

Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.

INOTROPIC THERAPY FOR BRIDGING

Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.

Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.⁷

CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES

Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.^8,9 The prognosis is not as good as for combined heart-lung transplantation patients.

Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.

Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.

The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.

Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.

Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.

Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.¹⁰

Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.^11,12 Case 1 (below) is an example of the problem.

Case 1: Poor outcome despite an ideal scenario

A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.

In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.

Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.

The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.

Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.

Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.

Coronary artery vasculopathy is still a major problem

This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.

Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.

THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED

The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.

All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.

In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:

• Local, status 1A
• Local, status 1B
• Zone A, status 1A
• Zone A, status 1B
• Local, status 2
• Zone B, status 1A
• Zone B, status 1B
• Zone A, status 2.

As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.³

The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.¹³ The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.

Heart transplant outcomes are publicly reported

The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.

Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.

MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?

Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.

Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.

Case 2: A good outcome despite a poor prognosis

A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.

Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.

LVADs continue to improve

Many devices are available for mechanical circulatory support.¹⁴ In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.

LVADs are of three types:

• Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
• Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
• Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.

The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.¹⁵ The results of such studies and the increased durability of the devices have led to their rapidly expanded use.

The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.¹⁶ In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.¹⁷

Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).¹⁸ Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.¹⁹ This study can be viewed as supporting the use of LVADs as destination therapy.

Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.²⁰

Adverse events with LVADs have improved, but continue to be of concern

Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.¹⁸

Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.

Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.²¹

Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.

Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.

Good data are kept on device outcomes

The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.

The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.²² The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.²³ An earlier report showed that the level of illness at the time of implantation predicts survival²⁴; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.

The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.

On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.

FUTURE DIRECTIONS

PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.

A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.

Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.

This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.

THE PREVALENCE OF HEART FAILURE

About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.¹ Patients with systolic heart failure can be classified by degree of severity under two systems:

The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.

The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.²

The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.³

WHICH AMBULATORY PATIENTS ARE MOST AT RISK?

The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.

The European Society of Cardiology⁴ developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:

• Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
• Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
• Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
• Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
• One or more hospitalizations for heart failure in the past 6 months.

Treadmill exercise time is an easily performed test. Hsich et al⁵ found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.

The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,⁶ but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).

Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.

INOTROPIC THERAPY FOR BRIDGING

Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.

Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.⁷

CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES

Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.^8,9 The prognosis is not as good as for combined heart-lung transplantation patients.

Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.

Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.

The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.

Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.

Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.

Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.¹⁰

Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.^11,12 Case 1 (below) is an example of the problem.

Case 1: Poor outcome despite an ideal scenario

A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.

In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.

Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.

The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.

Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.

Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.

Coronary artery vasculopathy is still a major problem

This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.

Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.

THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED

The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.

All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.

In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:

• Local, status 1A
• Local, status 1B
• Zone A, status 1A
• Zone A, status 1B
• Local, status 2
• Zone B, status 1A
• Zone B, status 1B
• Zone A, status 2.

As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.³

The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.¹³ The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.

Heart transplant outcomes are publicly reported

The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.

Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.

MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?

Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.

Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.

Case 2: A good outcome despite a poor prognosis

A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.

Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.

LVADs continue to improve

Many devices are available for mechanical circulatory support.¹⁴ In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.

LVADs are of three types:

• Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
• Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
• Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.

The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.¹⁵ The results of such studies and the increased durability of the devices have led to their rapidly expanded use.

The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.¹⁶ In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.¹⁷

Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).¹⁸ Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.¹⁹ This study can be viewed as supporting the use of LVADs as destination therapy.

Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.²⁰

Adverse events with LVADs have improved, but continue to be of concern

Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.¹⁸

Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.

Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.²¹

Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.

Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.

Good data are kept on device outcomes

The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.

The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.²² The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.²³ An earlier report showed that the level of illness at the time of implantation predicts survival²⁴; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.

The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.

On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.

FUTURE DIRECTIONS

PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.

A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.

A 47-year-old man presented with acute shortness of breath and chest and neck pain, which began after he heard popping sounds while boarding a bus. The pain was right-sided, sharp, worse with deep breathing, and associated with a sensation of fullness over the right chest.

His medical conditions included controlled hypertension, gastroesophageal reflux disease, and chronic obstructive pulmonary disease (COPD). The COPD was managed with an albuterol inhaler only. He had a 50-pack-year history of smoking, and he drank alcohol occasionally.

On arrival, he was in mild respiratory distress, but his vital signs were stable. We could hear wheezing on both sides of his chest and feel subcutaneous crepitation on both sides of his chest and neck, the latter more on the right side. The rest of the examination was unremarkable.

Results of a complete blood cell count and metabolic panel were within normal limits. Because of the above findings, nasopharyngeal radiogragraphy was ordered (Figures 1 and 2).

Q: What is the most likely cause of this presentation?

• Esophageal rupture
• Gas gangrene
• Asthma exacerbation
• Ruptured emphysematous bullae

A: This patient had a history of COPD, which put him at risk of developing bullous emphysematous bullae that can rupture and cause subcutaneous emphysema. His nasopharyngeal radiograph (Figure1) showed bilateral extensive subcutaneous emphysema. His lateral nasopharyngeal radiograph (Figure 2) showed air-tracking within the mediastinum and into the retropharyngeal space (arrow). Computed tomography (Figure 3) showed extensive subcutaneous emphysema in the right lateral chest wall (arrow) and large bullae in the right upper lobe (arrow heads). As for the other possibilities:

Esophageal ruptures and tears are iatrogenic in most cases and usually occur after endoscopic procedures, but they can also occur in patients with intractable vomiting. Computed tomography often shows esophageal thickening, periesophageal fluid, mediastinal widening, and extraluminal air. However, in most cases, it is seen as pneumomediastinum and subcutaneous emphysema.¹

Gas gangrene is a life-threatening soft-tissue and muscle infection caused by Clostridium perfringens in most cases.² The pain is out of proportion to the findings on physical examination. Patients usually have toxic signs and symptoms such as fever and hypotension. Our patient was hemodynamically stable, with no changes in skin color.

Severe exacerbations of asthma can lead to alveolar rupture, pneumothorax, and subcutaneous emphysema, although this is a rare complication. Air can dissect along the bronchovascular sheaths into the neck and cause subcutaneous emphysema, or into the pleural space and cause pneumothorax. Our patient had no history of asthma and plainly had emphysematous bullae.³

SUBCUTANEOUS EMPHYSEMA

Subcutaneous emphysema is a collection of air within subcutaneous tissues. It usually presents as bloating of the skin around the neck and the chest wall. It is often seen in patients with pneumothorax.

The most common cause of subcutaneous emphysema is traumatic injury to the chest wall, such as from a motor vehicle accident or a stab wound,⁴ but it can also occur spontaneously in patients who have severe emphysema with large bullae. As the emphysema progresses, the bullae can easily rupture, and this can lead to pneumothorax, which can lead to subcutaneous emphysema. Primary spontaneous pneumothorax and subcutaneous emphysema can occur in people who have unrecognized lung disease and genetic disorders such as Marfan syndrome and Ehler-Danlos syndrome.⁵ Other causes include iatrogenic injury, Pneumocystis jirovecii pneumonia (common in patients with human immunodeficiency virus infection), and cystic fibrosis. Pneumothorax occurs in about 30% of cases of P jirovecii pneumonia,⁶ and in about 6% of patients with cystic fibrosis.⁷ Bronchocutaneous fistula is an extremely rare complication of lung cancer and can cause subcutaneous emphysema.⁸ Tuberculosis is another possible cause.⁹

Subcutaneous emphysema mainly presents with chest or neck pain and wheezing. In severe cases, air can track to the face, causing facial swelling and difficulty breathing due to compression of the larynx. Also, it can track down to the thighs, causing leg pain and swelling.¹⁰

On examination, subcutaneous emphysema can be detected by palpating the chest wall, which causes the air bubble to move and produce crackling sounds. Most cases of subcutaneous emphysema are diagnosed clinically. Chest radiography and computed tomography help identify the source of air leak. Ultrasonography is usually used in cases of blunt trauma to the chest as part of the Focal Assessment With Sonography for Trauma protocol.¹¹

Subcutaneous emphysema can resolve spontaneously, requiring only pain management and supplemental oxygen.¹² In severe cases, air collection can lead to what is called “massive subcutaneous emphysema,” which requires surgical drainage.