We have seen significant growth in clinical research in critical care medicine in the last decade. Advances have been made in many important areas in this field; of these, advances in treating septic shock and acute respiratory distress syndrome (ARDS), and also in supportive therapies for critically ill patients (eg, sedatives, insulin), have perhaps received the most attention.

Of note, several once-established therapies in these areas have failed the test of time, as the result of evidence from more-recent clinical trials. For example, recent studies have shown that a pulmonary arterial catheter does not improve outcomes in patients with ARDS. Similarly, what used to be “optimal” fluid management in patients with ARDS is no longer considered appropriate.

In this review, we summarize eight major studies in critical care medicine published in the last 5 years, studies that have contributed to changes in our practice in the intensive care unit (ICU).

FLUID MANAGEMENT IN ARDS

Key points

• In patients with acute lung injury (ALI) and ARDS, fluid restriction is associated with better outcomes than a liberal fluid policy.
• A pulmonary arterial catheter is not necessary and, compared with a central venous catheter, may result in more complications in patients with ALI and ARDS.

Background

Fluid management practices in patients with ARDS have been extremely variable. Two different approaches are commonly used: the liberal or “wet” approach to optimize tissue perfusion and the “dry” approach, which focuses on reducing lung edema. Given that most deaths attributed to ARDS result from extrapulmonary organ failure, aggressive fluid restriction has been the less popular approach.

Additionally, although earlier studies and meta-analyses suggested that the use of a pulmonary arterial catheter was not associated with better outcomes in critically ill patients,¹ controversy remained regarding the value of a pulmonary arterial catheter compared with a central venous catheter in guiding fluid management in patients with ARDS, and data were insufficient to prove one strategy better than the other.

The Fluids and Catheter Treatment Trial (FACTT)

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK; WIEDEMANN HP, WHEELER AP, BERNARD GR, ET AL. COMPARISON OF TWO FLUID-MANAGEMENT STRATEGIES IN ACUTE LUNG INJURY. N ENGL J MED 2006; 354:2564–2575.

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK; WHEELER AP, BERNARD GR, THOMPSON BT, ET AL. PULMONARY-ARTERY VERSUS CENTRAL VENOUS CATHETER TO GUIDE TREATMENT OF ACUTE LUNG INJURY. N ENGL J MED 2006; 354:2213–2224.

The Fluids and Catheter Treatment Trial (FACTT) compared two fluid strategies² and also the utility of a pulmonary arterial catheter vs a central venous catheter³ in patients with ALI or ARDS.

This two-by-two factorial trial randomized 1,000 patients to be treated according to either a conservative (fluid-restrictive or “dry”) or a liberal (“wet”) fluid management strategy for 7 days. Additionally, they were randomly assigned to receive either a central venous catheter or a pulmonary arterial catheter. The trial thus had four treatment groups:

• Fluid-restricted and a central venous catheter, with a goal of keeping the central venous pressure below 4 mm Hg
• Fluid-restricted and a pulmonary arterial catheter: fluids were restricted and diuretics were given to keep the pulmonary artery occlusion pressure below 8 mm Hg
• Fluid-liberal and a central venous catheter: fluids were given to keep the central venous pressure between 10 and 14 mm Hg
• Fluid-liberal and a pulmonary arterial catheter: fluids were given to keep the pulmonary artery occlusion pressure between 14 and 18 mm Hg.

The primary end point was the mortality rate at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and parameters of lung physiology. All patients were managed with a low-tidal-volume strategy.

The ‘dry’ strategy was better

The cumulative fluid balance was −136 mL ± 491 mL in the “dry” group and 6,992 mL ± 502 mL in the “wet” group, a difference of more than 7 L (P < .0001). Of note, before randomization, the patients were already fluid-positive, with a mean total fluid balance of +2,700 mL).²

At 60 days, no statistically significant difference in mortality rate was seen between the fluid-management groups (25.5% in the dry group vs 28.4% in the wet group (P = .30). Nevertheless, patients in the dry group had better oxygenation indices and lung injury scores (including lower plateau airway pressure), resulting in more ventilator-free days (14.6 ± 0.5 vs 12.1 ± 0.5; P = .0002) and ICU-free days (13.4 ± 0.4 vs 11.2 ± 0.4; P = .0003).²

Although those in the dry-strategy group had a slightly lower cardiac index and mean arterial pressure, they did not have a higher incidence of shock.

More importantly, the dry group did not have a higher rate of nonpulmonary organ failure. Serum creatinine and blood urea nitrogen concentrations were slightly higher in this group, but this was not associated with a higher incidence of renal failure or the use of dialysis: 10% in the dry-strategy group vs 14% in the wet-strategy group; P = .0642).²

No advantage with a pulmonary arterial catheter

The mortality rate did not differ between the catheter groups. However, the patients who received a pulmonary arterial catheter stayed in the ICU 0.2 days longer and had twice as many nonfatal cardiac arrhythmias as those who received a central venous catheter.³

Comments

The liberal fluid-strategy group had fluid balances similar to those seen in previous National Institutes of Health ARDS Network trials in which fluid management was not controlled. This suggests that the liberal fluid strategy reflects usual clinical practice.

Although the goals used in this study (central venous pressure < 4 mm Hg or pulmonary artery occlusion pressure < 8 mm Hg) could be difficult to achieve in clinical practice, a conservative strategy of fluid management is preferred in patients with ALI or ARDS, given the benefits observed in this trial.

A pulmonary arterial catheter is not indicated to guide hemodynamic management of patients with ARDS.

 

CORTICOSTEROID USE IN ARDS

Key points

• In selected patients with ARDS, the prolonged use of corticosteroids may result in better oxygenation and a shorter duration of mechanical ventilation.
• Late use of corticosteroids in patients with ARDS (> 14 days after diagnosis) is not indicated and may increase the risk of death.
• The role of corticosteroids in early ARDS (< 7 days after diagnosis) remains controversial.

Background

Systemic corticosteroid therapy was commonly used in ARDS patients in the 1970s and 1980s. However, a single-center study published in the late 1980s showed that a corticosteroid in high doses (methylprednisolone 30 mg/kg) resulted in more complications and was not associated with a lower mortality rate.⁴ On the other hand, a small study that included only patients with persistent ARDS (defined as ARDS lasting for more than 7 days) subsequently showed that oxygenation was significantly better and that fewer patients died while in the hospital with the use of methylprednisolone 2 mg/kg for 32 days.⁵

In view of these divergent findings, the ARDS Network decided to perform a study to help understand the role of corticosteroids in ARDS.

The Late Steroid Rescue Study (LaSRS)

STEINBERG KP, HUDSON LD, GOODMAN RB, ET AL; NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK. EFFICACY AND SAFETY OF CORTICOSTEROIDS FOR PERSISTENT ACUTE RESPIRATORY DISTRESS SYNDROME. N ENGL J MED 2006; 354:1671–1684.

The Late Steroid Rescue Study (LaSRS),⁶ a double-blind, multicenter trial, randomly assigned 180 patients with persistent ARDS (defined as ongoing disease 7–28 days after its onset) to receive methylprednisolone or placebo for 21 days.

Methylprednisolone was given in an initial dose of 2 mg/kg of predicted body weight followed by a dose of 0.5 mg/kg every 6 hours for 14 days and then a dose of 0.5 mg/kg every 12 hours for 7 days, and then it was tapered over 2 to 4 days and discontinued. It could be discontinued if 21 days of treatment were completed or if the patient was able to breathe without assistance.

The primary end point was the mortality rate at 60 days. Secondary end points included the number of ventilator-free days, organ-failure-free days, and complications and the levels of biomarkers of inflammation.

No reduction in mortality rates with steroids

The mortality rates did not differ significantly in the corticosteroid group vs the placebo group at 60 days:

• 29.2% with methylprednisolone (95% confidence interval [CI] 20.8–39.4)
• 28.6% with placebo (95% CI 20.3–38.6, P = 1.0).

Mortality rates at 180 days were also similar between the groups:

• 31.5% with methylprednisolone (95% CI 22.8–41.7)
• 31.9% with placebo (95% CI 23.2–42.0, P = 1.0).

In patients randomized between 7 and 13 days after the onset of ARDS, the mortality rates were lower in the methylprednisolone group than in the placebo group but the differences were not statistically significant. The mortality rate in this subgroup was 27% vs 36% (P = .26) at 60 days and was 27% vs 39% (P = .14) at 180 days.

However, in patients randomized more than 14 days after the onset of ARDS, the mortality rate was significantly higher in the methylprednisolone group than in the placebo group at 60 days (35% vs 8%, P = .02) and at 180 days (44% vs 12%, P = .01).

Some benefit in secondary outcomes

At day 28, methylprednisolone was associated with:

• More ventilator-free days (11.2 ± 9.4 vs 6.8 ± 8.5, P < .001)
• More shock-free days (20.7 ± 8.9 vs 17.9 ± 10.2, P = .04)
• More ICU-free days (8.9 ± 8.2 vs 6.7 ± 7.8, P = .02).

Similarly, pulmonary physiologic indices were better with methylprednisolone, specifically:

• The ratio of Pao₂ to the fraction of inspired oxygen at days 3, 4, and 14 (P < .05)
• Plateau pressure at days 4, 5, and 7 (P < .05)
• Static compliance at days 7 and 14 (P < .05).

In terms of side effects, methylprednisolone was associated with more events associated with myopathy or neuropathy (9 vs 0, P = .001), but there were no differences in the number of serious infections or in glycemic control.

Comments

Although other recent studies suggested that corticosteroid use may be associated with a reduction in mortality rates,^7–9 LaSRS did not confirm this effect. Although the doses and length of therapy were similar in these studies, LaSRS was much larger and included patients from the ARDS Network.

Nevertheless, LaSRS was criticized because of strict exclusion criteria and poor enrollment (only 5% of eligible patients were included). Additionally, it was conducted over a period of time when some ICU practices varied significantly (eg, low vs high tidal volume ventilation, tight vs loose glucose control).

The role of corticosteroids in early ARDS (< 7 days after diagnosis) remains controversial at best. Table 1 summarizes recent studies that evaluated the use of corticosteroids in patients with ARDS.

INTERRUPTING SEDATION DURING MECHANICAL VENTILATION

Key points

• Daily awakening of mechanically ventilated patients is safe.
• Daily interruption of sedation in mechanically ventilated patients is associated with a shorter length of mechanical ventilation.

Background

Sedatives are a central component of critical care. Continuous infusions of narcotics, benzodiazepines, and anesthetic agents are frequently used to promote comfort in patients receiving mechanical ventilation.

Despite its widespread use in the ICU, there is little evidence that such sedation improves outcomes. Observational and randomized trials^10–12 have shown that patients who receive continuous infusions of sedatives need to be on mechanical ventilation longer than those who receive intermittent dosing. Additionally, an earlier randomized controlled trial¹³ showed that daily interruption of sedative drug infusions decreased the duration of mechanical ventilation by almost 50% and resulted in a reduction in the length of stay in the ICU.

Despite these findings, many ICU physicians remain skeptical of the value of daily interruption of sedative medications and question the safety of this practice.

The Awakening and Breathing Controlled (ABC) trial

GIRARD TD, KRESS JP, FUCHS BD, ET AL. EFFICACY AND SAFETY OF A PAIRED SEDATION AND VENTILATOR WEANING PROTOCOL FOR MECHANICALLY VENTILATED PATIENTS IN INTENSIVE CARE (AWAKENING AND BREATHING CONTROLLED TRIAL): A RANDOMISED CONTROLLED TRIAL. LANCET 2008; 371:126–134.

The Awakening and Breathing Controlled (ABC) trial¹⁴ was a multicenter, randomized controlled trial that included 336 patients who required at least 12 consecutive hours of mechanical ventilation. All patients had to be receiving patient-targeted sedation.

Those in the intervention group (n = 168) had their sedation interrupted every day, followed by a clinical assessment to determine whether they could be allowed to try breathing spontaneously. The control group (n = 168) also received a clinical assessment for a trial of spontaneous breathing, while their sedation was continued as usual.

In patients in the intervention group who failed the screening for a spontaneous breathing trial, the sedatives were resumed at half the previous dose. Criteria for failure on the spontaneous breathing trial included any of the following: anxiety, agitation, respiratory rate more than 35 breaths per minute for 5 minutes or longer, cardiac arrhythmia, oxygen saturation less than 88% for 5 minutes or longer, or two or more signs of respiratory distress, tachycardia, bradycardia, paradoxical breathing, accessory muscle use, diaphoresis, or marked dyspnea.

 

 

Interrupting sedation was superior

The combination of sedation interruption and a spontaneous breathing trial was superior to a spontaneous breathing trial alone. The mean number of ventilator-free days:

• 14.7 ± 0.9 with sedation interruption
• 11.6 ± 0.9 days with usual care (P = .02).

The median time to ICU discharge:

• 9.1 days with sedation interruption (interquartile range 5.1 to 17.8)
• 12.9 days with usual care (interquartile range 6.0 to 24.2, P = .01).

The mortality rate at 28 days:

• 28% with sedation interruption
• 35% with usual care (P = .21).

The mortality rate at 1 year:

• 44% with sedation interruption
• 58% with usual care (hazard ratio [HR] in the intervention group 0.68, 95% CI 0.50–0.92, P = .01).

Of note, patients in the intervention group had a higher rate of self-extubation (9.6% vs 3.6%, P = .03), but the rate of reintubation was similar between the groups (14% vs 13%, P = .47).

Comments

The addition of daily awakenings to spontaneous breathing trials results in a further reduction in the number of ICU days and increases the number of ventilator-free days.

Of note, the protocol allowed patients in the control group to undergo a spontaneous breathing trial while on sedatives (69% of the patients were receiving sedation at the time). Therefore, a bias effect in favor of the intervention group cannot be excluded. However, both groups had to meet criteria for readiness for spontaneous breathing.

The study demonstrates the safety of daily awakenings and confirms previous findings suggesting that a daily trial of spontaneous breathing results in better ICU outcomes.

GLUCOSE CONTROL IN THE ICU

Key points

• Although earlier studies suggested that intensive insulin therapy might be beneficial in critically ill patients, new findings show that strict glucose control can lead to complications without improving outcomes.

Background

A previous study¹⁵ found that intensive insulin therapy to maintain a blood glucose level between 80 and 110 mg/dL (compared with 180–200 mg/dL) reduced the mortality rate in surgical critical care patients. The mortality rate in the ICU was 4.6% with intensive insulin therapy vs 8.0% with conventional therapy (P < .04), and the effect was more robust for patients who remained longer than 5 days in the ICU (10.6% vs 20.2%).

Importantly, however, hypoglycemia (defined as blood glucose ≤ 40 mg/dL) occurred in 39 patients in the intensive-treatment group vs 6 patients in the conventional-treatment group.

The NICE-SUGAR trial

NICE-SUGAR STUDY INVESTIGATORS; FINFER S, CHITTOCK DR, SU SY, ET AL. INTENSIVE VERSUS CONVENTIONAL GLUCOSE CONTROL IN CRITICALLY ILL PATIENTS. N ENGL J MED 2009; 360:1283–1297.

The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial¹⁶ randomized 6,104 patients in medical and surgical ICUs to receive either intensive glucose control (blood glucose 81–108 mg/dL) with insulin therapy or conventional glucose control (blood glucose < 180 mg/dL). In the conventional-control group, insulin was discontinued if the blood glucose level dropped below 144 mg/dL.

A higher mortality rate with intensive glucose control

As expected, the intensive-control group achieved lower blood glucose levels: 115 vs 144 mg/dL.

Nevertheless, intensive glucose control was associated with a higher incidence of severe hypoglycemia, defined as a blood glucose level lower than 40 mg/dL: 6.8% vs 0.5%.

More importantly, compared with conventional insulin therapy, intensive glucose control was associated with a higher 90-day mortality rate: 27.5% vs 24.9% (odds ratio 1.14, 95% CI 1.02–1.28). These findings were similar in the subgroup of surgical patients (24.4% vs 19.8%, odds ratio 1.31, 95% CI 1.07–1.61).

Comments

Of note, the conventional-control group had more patients who discontinued the treatment protocol prematurely. Additionally, more patients in this group received corticosteroids.

These results widely differ from those of a previous study by van den Berghe et al,¹⁵ which showed that tight glycemic control is associated with a survival benefit. The differences in outcomes are probably largely related to different patient populations, as van den Berghe et al included patients who had undergone cardiac surgery, who were more likely to benefit from strict blood glucose control.

The VISEP trial

BRUNKHORST FM, ENGEL C, BLOOS F, ET AL; GERMAN COMPETENCE NETWORK SEPSIS (SEPNET). INTENSIVE INSULIN THERAPY AND PENTASTARCH RESUSCITATION IN SEVERE SEPSIS. N ENGL J MED 2008; 358:125–139.

The Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial was a multicenter study designed to compare intensive insulin therapy (target blood glucose level 80–110 mg/dL) and conventional glucose control (target blood glucose level 180–200 mg/dL) in patients with severe sepsis.¹⁷ It also compared two fluids for volume resuscitation: 10% pentastarch vs modified Ringer's lactate. It included both medical and surgical patients.

Trial halted early for safety reasons

The mean morning blood glucose level was significantly lower in the intensive insulin group (112 vs 151 mg/dL).

Severe hypoglycemia (blood glucose ≤ 40 mg/dL) was more common in the group that received intensive insulin therapy (17% vs 4.1%, P < .001).

Mortality rates at 28 days did not differ significantly: 24.7% with intensive control vs 26.0% with conventional glucose control. The mortality rate at 90 days was 39.7% in the intensive therapy group and 35.4% in the conventional therapy group, but the difference was not statistically significant.

The intensive insulin arm of the trial was stopped after 488 patients were enrolled because of a higher rate of hypoglycemia (12.1% vs 2.1%) and of serious adverse events (10.9% vs 5.2%).

Additionally, the fluid resuscitation arm of the study was suspended at the first planned interim analysis because of a higher risk of organ failure in the 10% pentastarch group.

 

CORTICOSTEROID THERAPY IN SEPTIC SHOCK

Key points

• Corticosteroid therapy improves hemodynamic outcomes in patients with severe septic shock.
• Although meta-analyses suggest the mortality rate is lower with corticosteroid therapy, there is not enough evidence from randomized controlled trials to prove that the use of low-dose corticosteroids lowers the mortality rate in patients with septic shock.
• The corticotropin (ACTH) stimulation test should not be used to determine the need for corticosteroids in patients with septic shock.

Background

A previous multicenter study,¹⁸ performed in France, found that the use of corticosteroids in patients with septic shock resulted in lower rates of death at 28 days, in the ICU, and in the hospital and a shorter time to vasopressor withdrawal. Nevertheless, the beneficial effects were not observed in patients with adequate adrenal reserve (based on an ACTH stimulation test).

This study was criticized because of a high mortality rate in the placebo group.

The CORTICUS study

SPRUNG CL, ANNANE D, KEH D, ET AL; CORTICUS STUDY GROUP. HYDROCORTISONE THERAPY FOR PATIENTS WITH SEPTIC SHOCK. N ENGL J MED 2008; 358:111–124.

The Corticosteroid Therapy of Septic Shock (CORTICUS) study was a multicenter trial that randomly assigned 499 patients with septic shock to receive hydrocortisone (50 mg intravenously every 6 hours for 5 days, followed by a 6-day taper period) or placebo.¹⁹

Patients were eligible to be enrolled within 72 hours of onset of shock. Similar to previous studies, the CORTICUS trial classified patients on the basis of an ACTH stimulation test as having inadequate adrenal reserve (a cortisol increase of ≤ 9 μg/dL) or adequate adrenal reserve (a cortisol increase of > 9 μg/dL).

Faster reversal of shock with steroids

At baseline, the mean Simplified Acute Physiologic Score II (SAPS II) was 49 (the range of possible scores is 0 to 163; the higher the score the worse the organ dysfunction).

Hydrocortisone use resulted in a shorter duration of vasopressor use and a faster reversal of shock (3.3 days vs 5.8 days, P < .001).

This association was the same when patients were divided according to response to ACTH stimulation test. Time to reversal of shock in responders:

• 2.8 days with hydrocortisone
• 5.8 days with placebo (P < .001).

Time to reversal of shock in nonresponders:

• 3.9 days with hydrocortisone
• 6.0 days with placebo (P = .06).

Nevertheless, the treatment did not reduce the mortality rate at 28 days overall (34.3% vs 31.5% P = .51), or in the subgroups based on response to ACTH, or at any other time point. A post hoc analysis suggested that patients who had a systolic blood pressure of less than 90 mm Hg within 30 minutes of enrollment had a greater benefit in terms of mortality rate, but the effect was not statistically significant: the absolute difference was −11.2% (P = 0.28). Similarly, post hoc analyses also revealed a higher rate of death at 28 days in patients who received etomidate (Amidate) before randomization in both groups (P = .03).

Importantly, patients who received corticosteroids had a higher incidence of superinfections, including new episodes of sepsis or septic shock, with a combined odds ratio of 1.37 (95% CI 1.05–1.79).

Length of stay in the hospital or in the ICU was similar in patients who received corticosteroids and in those who received placebo. The ICU length of stay was 19 ± 31 days with hydrocortisone vs 18 ± 17 days with placebo (P = .51).

Comments

The CORTICUS trial showed that low-dose corticosteroid therapy results in faster reversal of shock in patients with severe septic shock. The hemodynamic benefits are present in all patients regardless of response to the ACTH stimulation test.

Nevertheless, contrary to previous findings,¹⁸ corticosteroid use was not associated with an improvement in mortality rates. Important differences exist between these two studies:

• The mortality rates in the placebo groups were significantly different (> 50% in the French study vs 30% in CORTICUS).
• The SAPS II scores were different in these two trials (55 vs 49), suggesting a greater severity of illness in the French study.
• The criteria for enrollment were different: the French study included patients who had a systolic blood pressure lower than 90 mm Hg for more than 1 hour despite fluid administration and vasopressor use, whereas the CORTICUS trial included patients who had a systolic blood pressure lower than 90 mm Hg for more than 1 hour despite fluid administration or vasopressor use.
• The time of enrollment was different: patients were enrolled much faster in the French study (within 8 hours) than in the CORTICUS trial (within 72 hours).

A recent meta-analysis of 17 randomized trials (including the CORTICUS study), found that, compared with those who received placebo, patients who received corticosteroids had a small reduction in the 28-day mortality rate (HR 0.84, 95% CI 0.71–1.00, P < .05).²⁰ Of note, this meta-analysis has been criticized for possible publication bias and also for a large degree of heterogeneity in its results.²¹

 

VASOPRESSOR THERAPY IN SHOCK

Key points

• Vasopressin use in patients with severe septic shock is not associated with an improvement in mortality rates.
• Vasopressin should not be used as a first-line agent in patients with septic shock.
• Norepinephrine should be considered a first-line agent in patients with shock.
• Compared with norepinephrine, the use of dopamine in patients with shock is associated with similar mortality rates, although its use may result in a greater number of cardiac adverse events.

Background

Vasopressin gained popularity in critical care in the last 10 years because several small studies showed that adding it improves hemodynamics and results in a reduction in the doses of catecholamines in patients with refractory septic shock.²² Furthermore, the Surviving Sepsis Campaign guidelines recommended the use of vasopressin in patients who have refractory shock despite fluid resuscitation and the use of other “conventional” vasopressors.²³

Despite these positive findings, it remained unknown if the use of vasopressin increases the survival rate in patients with septic shock.

The Vasopressin and Septic Shock Trial (VASST)

RUSSELL JA, WALLEY KR, SINGER J, ET AL; VASST INVESTIGATORS. VASOPRESSIN VERSUS NOREPINEPHRINE INFUSION IN PATIENTS WITH SEPTIC SHOCK. N ENGL J MED 2008; 358:877–887.

The Vasopressin and Septic Shock Trial (VASST)²⁴ was a multicenter randomized, double-blind, controlled trial that included 778 patients with refractory septic shock. Refractory shock was defined as the lack of a response to a normal saline fluid bolus of 500 mL or the need for vasopressors (norepinephrine in doses of at least 5 μg/minute or its equivalent for 6 hours or more in the 24 hours before randomization).

Two subgroups were identified: those with severe septic shock (requiring norepinephrine in doses of 15 μg/minute or higher) and those with less-severe septic shock (needing norepinephrine in doses of 5 to 14 μg/minute). Patients with unstable coronary artery disease (acute myocardial infarction, angina) and severe congestive heart failure were excluded.

Patients were randomized to receive an intravenous infusion of vasopressin (0.01–0.03 U/minute) or norepinephrine (5–15 mg/minute) in addition to open-labeled vasopressors (excluding vasopressin). The primary outcome was the all-cause mortality rate at 28 days.

Results

At 28 days, fewer patients had died in the vasopressin group than in the norepinephrine group (35.4% vs 39.3%), but the difference was not statistically significant (P = .26). The trend was the same at 90 days (mortality rate 43.9% vs 49.6%, P = .11).

Subgroup analysis showed that in patients with less-severe septic shock, those who received vasopressin had a lower mortality rate at 28 days (26.5% vs 35.7%, P = .05; relative risk 0.74; 95% CI 0.55–1.01) and at 90 days (35.8% vs 46.1%, P = .04; relative risk 0.78, 95% CI 0.61–0.99).

There were no statistically significant differences in any of the other secondary outcomes or in serious adverse events.

Comments

The study has been criticized for several reasons:

• The mean arterial blood pressure at baseline before initiation of vasopressin was 72 mm Hg (and some argue that vasopressin was therefore not needed by the time it was started).
• The time from screening to infusion of the study drug was very long (12 hours).
• The observed mortality rate was lower than expected (37%).

Despite these considerations, the VASST trial showed that vasopressin is not associated with an increased number of adverse events in patients without active cardiovascular disease. The possible benefit in terms of the mortality rate in the subgroup of patients with less-severe septic shock requires further investigation.

Is dopamine equivalent to norepinephrine?

Previously, the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a multicenter, observational cohort study, found that dopamine use was associated with a higher all-cause mortality rate in the ICU compared with no dopamine.²⁵ This finding had not been reproduced, as few well-designed studies had compared the effects of dopamine and norepinephrine.

The SOAP II study

DE BACKER D, BISTON P, DEVRIENDT J, ET AL; SOAP II INVESTIGATORS.. COMPARISON OF DOPAMINE AND NOREPINEPHRINE IN THE TREATMENT OF SHOCK. N ENGL J MED 2010; 362:779–789.

The SOAP II study,²⁶ a multicenter, randomized trial, compared dopamine vs norepinephrine as first-line vasopressor therapy. In patients with refractory shock despite use of dopamine 20 μg/kg/minute or norepinephrine 0.19 μg/kg/minute, open-label norepinephrine, epinephrine, or vasopressin was added.

The primary outcome was the mortality rate at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events.

Results

A total of 1,679 patients were included; 858 were assigned to dopamine and 821 to norepinephrine. Most (1,044, 62%) of the patients had a diagnosis of septic shock.

No significant difference in mortality rates was noted at 28 days: 52.5% with dopamine vs 48.5% with norepinephrine (P = .10).

However, there were more arrhythmias in the patients treated with dopamine: 207 events (24.1%) vs 102 events (12.4%) (P < .001). The number of other adverse events such as renal failure, myocardial infarction, arterial occlusion, or skin necrosis was not different between the groups.

A subgroup analysis showed that dopamine was associated with more deaths at 28 days in patients with cardiogenic shock (P = .03) but not in patients with septic shock (P = .19) or with hypovolemic shock (P = .84).

Comments

The study was criticized because the patients may not have received adequate fluid resuscitation (the study considered adequate resuscitation to be equivalent to 1 L of crystalloids or 500 mL of colloids), as different degrees of volume depletion among patients make direct comparisons of vasopressor effects difficult.

Additionally, the study defined dopamine 20 μg/kg/minute as being equipotent with norepinephrine 0.19 μg/kg/minute. Comparisons of potency between drugs are difficult to establish, as there are no available data.

Nevertheless, this study further confirms previous findings suggesting that norepinephrine is not associated with more end-organ damage (such as renal failure or skin ischemia), and shows that dopamine may increase the number of adverse events, particularly in patients with cardiac disease.

We have seen significant growth in clinical research in critical care medicine in the last decade. Advances have been made in many important areas in this field; of these, advances in treating septic shock and acute respiratory distress syndrome (ARDS), and also in supportive therapies for critically ill patients (eg, sedatives, insulin), have perhaps received the most attention.

Of note, several once-established therapies in these areas have failed the test of time, as the result of evidence from more-recent clinical trials. For example, recent studies have shown that a pulmonary arterial catheter does not improve outcomes in patients with ARDS. Similarly, what used to be “optimal” fluid management in patients with ARDS is no longer considered appropriate.

In this review, we summarize eight major studies in critical care medicine published in the last 5 years, studies that have contributed to changes in our practice in the intensive care unit (ICU).

FLUID MANAGEMENT IN ARDS

Key points

• In patients with acute lung injury (ALI) and ARDS, fluid restriction is associated with better outcomes than a liberal fluid policy.
• A pulmonary arterial catheter is not necessary and, compared with a central venous catheter, may result in more complications in patients with ALI and ARDS.

Background

Fluid management practices in patients with ARDS have been extremely variable. Two different approaches are commonly used: the liberal or “wet” approach to optimize tissue perfusion and the “dry” approach, which focuses on reducing lung edema. Given that most deaths attributed to ARDS result from extrapulmonary organ failure, aggressive fluid restriction has been the less popular approach.

Additionally, although earlier studies and meta-analyses suggested that the use of a pulmonary arterial catheter was not associated with better outcomes in critically ill patients,¹ controversy remained regarding the value of a pulmonary arterial catheter compared with a central venous catheter in guiding fluid management in patients with ARDS, and data were insufficient to prove one strategy better than the other.

The Fluids and Catheter Treatment Trial (FACTT)

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK; WIEDEMANN HP, WHEELER AP, BERNARD GR, ET AL. COMPARISON OF TWO FLUID-MANAGEMENT STRATEGIES IN ACUTE LUNG INJURY. N ENGL J MED 2006; 354:2564–2575.

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK; WHEELER AP, BERNARD GR, THOMPSON BT, ET AL. PULMONARY-ARTERY VERSUS CENTRAL VENOUS CATHETER TO GUIDE TREATMENT OF ACUTE LUNG INJURY. N ENGL J MED 2006; 354:2213–2224.

The Fluids and Catheter Treatment Trial (FACTT) compared two fluid strategies² and also the utility of a pulmonary arterial catheter vs a central venous catheter³ in patients with ALI or ARDS.

This two-by-two factorial trial randomized 1,000 patients to be treated according to either a conservative (fluid-restrictive or “dry”) or a liberal (“wet”) fluid management strategy for 7 days. Additionally, they were randomly assigned to receive either a central venous catheter or a pulmonary arterial catheter. The trial thus had four treatment groups:

• Fluid-restricted and a central venous catheter, with a goal of keeping the central venous pressure below 4 mm Hg
• Fluid-restricted and a pulmonary arterial catheter: fluids were restricted and diuretics were given to keep the pulmonary artery occlusion pressure below 8 mm Hg
• Fluid-liberal and a central venous catheter: fluids were given to keep the central venous pressure between 10 and 14 mm Hg
• Fluid-liberal and a pulmonary arterial catheter: fluids were given to keep the pulmonary artery occlusion pressure between 14 and 18 mm Hg.

The primary end point was the mortality rate at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and parameters of lung physiology. All patients were managed with a low-tidal-volume strategy.

The ‘dry’ strategy was better

The cumulative fluid balance was −136 mL ± 491 mL in the “dry” group and 6,992 mL ± 502 mL in the “wet” group, a difference of more than 7 L (P < .0001). Of note, before randomization, the patients were already fluid-positive, with a mean total fluid balance of +2,700 mL).²

At 60 days, no statistically significant difference in mortality rate was seen between the fluid-management groups (25.5% in the dry group vs 28.4% in the wet group (P = .30). Nevertheless, patients in the dry group had better oxygenation indices and lung injury scores (including lower plateau airway pressure), resulting in more ventilator-free days (14.6 ± 0.5 vs 12.1 ± 0.5; P = .0002) and ICU-free days (13.4 ± 0.4 vs 11.2 ± 0.4; P = .0003).²

Although those in the dry-strategy group had a slightly lower cardiac index and mean arterial pressure, they did not have a higher incidence of shock.

More importantly, the dry group did not have a higher rate of nonpulmonary organ failure. Serum creatinine and blood urea nitrogen concentrations were slightly higher in this group, but this was not associated with a higher incidence of renal failure or the use of dialysis: 10% in the dry-strategy group vs 14% in the wet-strategy group; P = .0642).²

No advantage with a pulmonary arterial catheter

The mortality rate did not differ between the catheter groups. However, the patients who received a pulmonary arterial catheter stayed in the ICU 0.2 days longer and had twice as many nonfatal cardiac arrhythmias as those who received a central venous catheter.³

Comments

The liberal fluid-strategy group had fluid balances similar to those seen in previous National Institutes of Health ARDS Network trials in which fluid management was not controlled. This suggests that the liberal fluid strategy reflects usual clinical practice.

Although the goals used in this study (central venous pressure < 4 mm Hg or pulmonary artery occlusion pressure < 8 mm Hg) could be difficult to achieve in clinical practice, a conservative strategy of fluid management is preferred in patients with ALI or ARDS, given the benefits observed in this trial.

A pulmonary arterial catheter is not indicated to guide hemodynamic management of patients with ARDS.

 

CORTICOSTEROID USE IN ARDS

Key points

• In selected patients with ARDS, the prolonged use of corticosteroids may result in better oxygenation and a shorter duration of mechanical ventilation.
• Late use of corticosteroids in patients with ARDS (> 14 days after diagnosis) is not indicated and may increase the risk of death.
• The role of corticosteroids in early ARDS (< 7 days after diagnosis) remains controversial.

Background

Systemic corticosteroid therapy was commonly used in ARDS patients in the 1970s and 1980s. However, a single-center study published in the late 1980s showed that a corticosteroid in high doses (methylprednisolone 30 mg/kg) resulted in more complications and was not associated with a lower mortality rate.⁴ On the other hand, a small study that included only patients with persistent ARDS (defined as ARDS lasting for more than 7 days) subsequently showed that oxygenation was significantly better and that fewer patients died while in the hospital with the use of methylprednisolone 2 mg/kg for 32 days.⁵

In view of these divergent findings, the ARDS Network decided to perform a study to help understand the role of corticosteroids in ARDS.

The Late Steroid Rescue Study (LaSRS)

STEINBERG KP, HUDSON LD, GOODMAN RB, ET AL; NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK. EFFICACY AND SAFETY OF CORTICOSTEROIDS FOR PERSISTENT ACUTE RESPIRATORY DISTRESS SYNDROME. N ENGL J MED 2006; 354:1671–1684.

The Late Steroid Rescue Study (LaSRS),⁶ a double-blind, multicenter trial, randomly assigned 180 patients with persistent ARDS (defined as ongoing disease 7–28 days after its onset) to receive methylprednisolone or placebo for 21 days.

Methylprednisolone was given in an initial dose of 2 mg/kg of predicted body weight followed by a dose of 0.5 mg/kg every 6 hours for 14 days and then a dose of 0.5 mg/kg every 12 hours for 7 days, and then it was tapered over 2 to 4 days and discontinued. It could be discontinued if 21 days of treatment were completed or if the patient was able to breathe without assistance.

The primary end point was the mortality rate at 60 days. Secondary end points included the number of ventilator-free days, organ-failure-free days, and complications and the levels of biomarkers of inflammation.

No reduction in mortality rates with steroids

The mortality rates did not differ significantly in the corticosteroid group vs the placebo group at 60 days:

• 29.2% with methylprednisolone (95% confidence interval [CI] 20.8–39.4)
• 28.6% with placebo (95% CI 20.3–38.6, P = 1.0).

Mortality rates at 180 days were also similar between the groups:

• 31.5% with methylprednisolone (95% CI 22.8–41.7)
• 31.9% with placebo (95% CI 23.2–42.0, P = 1.0).

In patients randomized between 7 and 13 days after the onset of ARDS, the mortality rates were lower in the methylprednisolone group than in the placebo group but the differences were not statistically significant. The mortality rate in this subgroup was 27% vs 36% (P = .26) at 60 days and was 27% vs 39% (P = .14) at 180 days.

However, in patients randomized more than 14 days after the onset of ARDS, the mortality rate was significantly higher in the methylprednisolone group than in the placebo group at 60 days (35% vs 8%, P = .02) and at 180 days (44% vs 12%, P = .01).

Some benefit in secondary outcomes

At day 28, methylprednisolone was associated with:

• More ventilator-free days (11.2 ± 9.4 vs 6.8 ± 8.5, P < .001)
• More shock-free days (20.7 ± 8.9 vs 17.9 ± 10.2, P = .04)
• More ICU-free days (8.9 ± 8.2 vs 6.7 ± 7.8, P = .02).

Similarly, pulmonary physiologic indices were better with methylprednisolone, specifically:

• The ratio of Pao₂ to the fraction of inspired oxygen at days 3, 4, and 14 (P < .05)
• Plateau pressure at days 4, 5, and 7 (P < .05)
• Static compliance at days 7 and 14 (P < .05).

In terms of side effects, methylprednisolone was associated with more events associated with myopathy or neuropathy (9 vs 0, P = .001), but there were no differences in the number of serious infections or in glycemic control.

Comments

Although other recent studies suggested that corticosteroid use may be associated with a reduction in mortality rates,^7–9 LaSRS did not confirm this effect. Although the doses and length of therapy were similar in these studies, LaSRS was much larger and included patients from the ARDS Network.

Nevertheless, LaSRS was criticized because of strict exclusion criteria and poor enrollment (only 5% of eligible patients were included). Additionally, it was conducted over a period of time when some ICU practices varied significantly (eg, low vs high tidal volume ventilation, tight vs loose glucose control).

The role of corticosteroids in early ARDS (< 7 days after diagnosis) remains controversial at best. Table 1 summarizes recent studies that evaluated the use of corticosteroids in patients with ARDS.

INTERRUPTING SEDATION DURING MECHANICAL VENTILATION

Key points

• Daily awakening of mechanically ventilated patients is safe.
• Daily interruption of sedation in mechanically ventilated patients is associated with a shorter length of mechanical ventilation.

Background

Sedatives are a central component of critical care. Continuous infusions of narcotics, benzodiazepines, and anesthetic agents are frequently used to promote comfort in patients receiving mechanical ventilation.

Despite its widespread use in the ICU, there is little evidence that such sedation improves outcomes. Observational and randomized trials^10–12 have shown that patients who receive continuous infusions of sedatives need to be on mechanical ventilation longer than those who receive intermittent dosing. Additionally, an earlier randomized controlled trial¹³ showed that daily interruption of sedative drug infusions decreased the duration of mechanical ventilation by almost 50% and resulted in a reduction in the length of stay in the ICU.

Despite these findings, many ICU physicians remain skeptical of the value of daily interruption of sedative medications and question the safety of this practice.

The Awakening and Breathing Controlled (ABC) trial

GIRARD TD, KRESS JP, FUCHS BD, ET AL. EFFICACY AND SAFETY OF A PAIRED SEDATION AND VENTILATOR WEANING PROTOCOL FOR MECHANICALLY VENTILATED PATIENTS IN INTENSIVE CARE (AWAKENING AND BREATHING CONTROLLED TRIAL): A RANDOMISED CONTROLLED TRIAL. LANCET 2008; 371:126–134.

The Awakening and Breathing Controlled (ABC) trial¹⁴ was a multicenter, randomized controlled trial that included 336 patients who required at least 12 consecutive hours of mechanical ventilation. All patients had to be receiving patient-targeted sedation.

Those in the intervention group (n = 168) had their sedation interrupted every day, followed by a clinical assessment to determine whether they could be allowed to try breathing spontaneously. The control group (n = 168) also received a clinical assessment for a trial of spontaneous breathing, while their sedation was continued as usual.

In patients in the intervention group who failed the screening for a spontaneous breathing trial, the sedatives were resumed at half the previous dose. Criteria for failure on the spontaneous breathing trial included any of the following: anxiety, agitation, respiratory rate more than 35 breaths per minute for 5 minutes or longer, cardiac arrhythmia, oxygen saturation less than 88% for 5 minutes or longer, or two or more signs of respiratory distress, tachycardia, bradycardia, paradoxical breathing, accessory muscle use, diaphoresis, or marked dyspnea.

 

 

Interrupting sedation was superior

The combination of sedation interruption and a spontaneous breathing trial was superior to a spontaneous breathing trial alone. The mean number of ventilator-free days:

• 14.7 ± 0.9 with sedation interruption
• 11.6 ± 0.9 days with usual care (P = .02).

The median time to ICU discharge:

• 9.1 days with sedation interruption (interquartile range 5.1 to 17.8)
• 12.9 days with usual care (interquartile range 6.0 to 24.2, P = .01).

The mortality rate at 28 days:

• 28% with sedation interruption
• 35% with usual care (P = .21).

The mortality rate at 1 year:

• 44% with sedation interruption
• 58% with usual care (hazard ratio [HR] in the intervention group 0.68, 95% CI 0.50–0.92, P = .01).

Of note, patients in the intervention group had a higher rate of self-extubation (9.6% vs 3.6%, P = .03), but the rate of reintubation was similar between the groups (14% vs 13%, P = .47).

Comments

The addition of daily awakenings to spontaneous breathing trials results in a further reduction in the number of ICU days and increases the number of ventilator-free days.

Of note, the protocol allowed patients in the control group to undergo a spontaneous breathing trial while on sedatives (69% of the patients were receiving sedation at the time). Therefore, a bias effect in favor of the intervention group cannot be excluded. However, both groups had to meet criteria for readiness for spontaneous breathing.

The study demonstrates the safety of daily awakenings and confirms previous findings suggesting that a daily trial of spontaneous breathing results in better ICU outcomes.

GLUCOSE CONTROL IN THE ICU

Key points

• Although earlier studies suggested that intensive insulin therapy might be beneficial in critically ill patients, new findings show that strict glucose control can lead to complications without improving outcomes.

Background

A previous study¹⁵ found that intensive insulin therapy to maintain a blood glucose level between 80 and 110 mg/dL (compared with 180–200 mg/dL) reduced the mortality rate in surgical critical care patients. The mortality rate in the ICU was 4.6% with intensive insulin therapy vs 8.0% with conventional therapy (P < .04), and the effect was more robust for patients who remained longer than 5 days in the ICU (10.6% vs 20.2%).

Importantly, however, hypoglycemia (defined as blood glucose ≤ 40 mg/dL) occurred in 39 patients in the intensive-treatment group vs 6 patients in the conventional-treatment group.

The NICE-SUGAR trial

NICE-SUGAR STUDY INVESTIGATORS; FINFER S, CHITTOCK DR, SU SY, ET AL. INTENSIVE VERSUS CONVENTIONAL GLUCOSE CONTROL IN CRITICALLY ILL PATIENTS. N ENGL J MED 2009; 360:1283–1297.

The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial¹⁶ randomized 6,104 patients in medical and surgical ICUs to receive either intensive glucose control (blood glucose 81–108 mg/dL) with insulin therapy or conventional glucose control (blood glucose < 180 mg/dL). In the conventional-control group, insulin was discontinued if the blood glucose level dropped below 144 mg/dL.

A higher mortality rate with intensive glucose control

As expected, the intensive-control group achieved lower blood glucose levels: 115 vs 144 mg/dL.

Nevertheless, intensive glucose control was associated with a higher incidence of severe hypoglycemia, defined as a blood glucose level lower than 40 mg/dL: 6.8% vs 0.5%.

More importantly, compared with conventional insulin therapy, intensive glucose control was associated with a higher 90-day mortality rate: 27.5% vs 24.9% (odds ratio 1.14, 95% CI 1.02–1.28). These findings were similar in the subgroup of surgical patients (24.4% vs 19.8%, odds ratio 1.31, 95% CI 1.07–1.61).

Comments

Of note, the conventional-control group had more patients who discontinued the treatment protocol prematurely. Additionally, more patients in this group received corticosteroids.

These results widely differ from those of a previous study by van den Berghe et al,¹⁵ which showed that tight glycemic control is associated with a survival benefit. The differences in outcomes are probably largely related to different patient populations, as van den Berghe et al included patients who had undergone cardiac surgery, who were more likely to benefit from strict blood glucose control.

The VISEP trial

BRUNKHORST FM, ENGEL C, BLOOS F, ET AL; GERMAN COMPETENCE NETWORK SEPSIS (SEPNET). INTENSIVE INSULIN THERAPY AND PENTASTARCH RESUSCITATION IN SEVERE SEPSIS. N ENGL J MED 2008; 358:125–139.

The Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial was a multicenter study designed to compare intensive insulin therapy (target blood glucose level 80–110 mg/dL) and conventional glucose control (target blood glucose level 180–200 mg/dL) in patients with severe sepsis.¹⁷ It also compared two fluids for volume resuscitation: 10% pentastarch vs modified Ringer's lactate. It included both medical and surgical patients.

Trial halted early for safety reasons

The mean morning blood glucose level was significantly lower in the intensive insulin group (112 vs 151 mg/dL).

Severe hypoglycemia (blood glucose ≤ 40 mg/dL) was more common in the group that received intensive insulin therapy (17% vs 4.1%, P < .001).

Mortality rates at 28 days did not differ significantly: 24.7% with intensive control vs 26.0% with conventional glucose control. The mortality rate at 90 days was 39.7% in the intensive therapy group and 35.4% in the conventional therapy group, but the difference was not statistically significant.

The intensive insulin arm of the trial was stopped after 488 patients were enrolled because of a higher rate of hypoglycemia (12.1% vs 2.1%) and of serious adverse events (10.9% vs 5.2%).

Additionally, the fluid resuscitation arm of the study was suspended at the first planned interim analysis because of a higher risk of organ failure in the 10% pentastarch group.

 

CORTICOSTEROID THERAPY IN SEPTIC SHOCK

Key points

• Corticosteroid therapy improves hemodynamic outcomes in patients with severe septic shock.
• Although meta-analyses suggest the mortality rate is lower with corticosteroid therapy, there is not enough evidence from randomized controlled trials to prove that the use of low-dose corticosteroids lowers the mortality rate in patients with septic shock.
• The corticotropin (ACTH) stimulation test should not be used to determine the need for corticosteroids in patients with septic shock.

Background

A previous multicenter study,¹⁸ performed in France, found that the use of corticosteroids in patients with septic shock resulted in lower rates of death at 28 days, in the ICU, and in the hospital and a shorter time to vasopressor withdrawal. Nevertheless, the beneficial effects were not observed in patients with adequate adrenal reserve (based on an ACTH stimulation test).

This study was criticized because of a high mortality rate in the placebo group.

The CORTICUS study

SPRUNG CL, ANNANE D, KEH D, ET AL; CORTICUS STUDY GROUP. HYDROCORTISONE THERAPY FOR PATIENTS WITH SEPTIC SHOCK. N ENGL J MED 2008; 358:111–124.

The Corticosteroid Therapy of Septic Shock (CORTICUS) study was a multicenter trial that randomly assigned 499 patients with septic shock to receive hydrocortisone (50 mg intravenously every 6 hours for 5 days, followed by a 6-day taper period) or placebo.¹⁹

Patients were eligible to be enrolled within 72 hours of onset of shock. Similar to previous studies, the CORTICUS trial classified patients on the basis of an ACTH stimulation test as having inadequate adrenal reserve (a cortisol increase of ≤ 9 μg/dL) or adequate adrenal reserve (a cortisol increase of > 9 μg/dL).

Faster reversal of shock with steroids

At baseline, the mean Simplified Acute Physiologic Score II (SAPS II) was 49 (the range of possible scores is 0 to 163; the higher the score the worse the organ dysfunction).

Hydrocortisone use resulted in a shorter duration of vasopressor use and a faster reversal of shock (3.3 days vs 5.8 days, P < .001).

This association was the same when patients were divided according to response to ACTH stimulation test. Time to reversal of shock in responders:

• 2.8 days with hydrocortisone
• 5.8 days with placebo (P < .001).

Time to reversal of shock in nonresponders:

• 3.9 days with hydrocortisone
• 6.0 days with placebo (P = .06).

Nevertheless, the treatment did not reduce the mortality rate at 28 days overall (34.3% vs 31.5% P = .51), or in the subgroups based on response to ACTH, or at any other time point. A post hoc analysis suggested that patients who had a systolic blood pressure of less than 90 mm Hg within 30 minutes of enrollment had a greater benefit in terms of mortality rate, but the effect was not statistically significant: the absolute difference was −11.2% (P = 0.28). Similarly, post hoc analyses also revealed a higher rate of death at 28 days in patients who received etomidate (Amidate) before randomization in both groups (P = .03).

Importantly, patients who received corticosteroids had a higher incidence of superinfections, including new episodes of sepsis or septic shock, with a combined odds ratio of 1.37 (95% CI 1.05–1.79).

Length of stay in the hospital or in the ICU was similar in patients who received corticosteroids and in those who received placebo. The ICU length of stay was 19 ± 31 days with hydrocortisone vs 18 ± 17 days with placebo (P = .51).

Comments

The CORTICUS trial showed that low-dose corticosteroid therapy results in faster reversal of shock in patients with severe septic shock. The hemodynamic benefits are present in all patients regardless of response to the ACTH stimulation test.

Nevertheless, contrary to previous findings,¹⁸ corticosteroid use was not associated with an improvement in mortality rates. Important differences exist between these two studies:

• The mortality rates in the placebo groups were significantly different (> 50% in the French study vs 30% in CORTICUS).
• The SAPS II scores were different in these two trials (55 vs 49), suggesting a greater severity of illness in the French study.
• The criteria for enrollment were different: the French study included patients who had a systolic blood pressure lower than 90 mm Hg for more than 1 hour despite fluid administration and vasopressor use, whereas the CORTICUS trial included patients who had a systolic blood pressure lower than 90 mm Hg for more than 1 hour despite fluid administration or vasopressor use.
• The time of enrollment was different: patients were enrolled much faster in the French study (within 8 hours) than in the CORTICUS trial (within 72 hours).

A recent meta-analysis of 17 randomized trials (including the CORTICUS study), found that, compared with those who received placebo, patients who received corticosteroids had a small reduction in the 28-day mortality rate (HR 0.84, 95% CI 0.71–1.00, P < .05).²⁰ Of note, this meta-analysis has been criticized for possible publication bias and also for a large degree of heterogeneity in its results.²¹

 

VASOPRESSOR THERAPY IN SHOCK

Key points

• Vasopressin use in patients with severe septic shock is not associated with an improvement in mortality rates.
• Vasopressin should not be used as a first-line agent in patients with septic shock.
• Norepinephrine should be considered a first-line agent in patients with shock.
• Compared with norepinephrine, the use of dopamine in patients with shock is associated with similar mortality rates, although its use may result in a greater number of cardiac adverse events.

Background

Vasopressin gained popularity in critical care in the last 10 years because several small studies showed that adding it improves hemodynamics and results in a reduction in the doses of catecholamines in patients with refractory septic shock.²² Furthermore, the Surviving Sepsis Campaign guidelines recommended the use of vasopressin in patients who have refractory shock despite fluid resuscitation and the use of other “conventional” vasopressors.²³

Despite these positive findings, it remained unknown if the use of vasopressin increases the survival rate in patients with septic shock.

The Vasopressin and Septic Shock Trial (VASST)

RUSSELL JA, WALLEY KR, SINGER J, ET AL; VASST INVESTIGATORS. VASOPRESSIN VERSUS NOREPINEPHRINE INFUSION IN PATIENTS WITH SEPTIC SHOCK. N ENGL J MED 2008; 358:877–887.

The Vasopressin and Septic Shock Trial (VASST)²⁴ was a multicenter randomized, double-blind, controlled trial that included 778 patients with refractory septic shock. Refractory shock was defined as the lack of a response to a normal saline fluid bolus of 500 mL or the need for vasopressors (norepinephrine in doses of at least 5 μg/minute or its equivalent for 6 hours or more in the 24 hours before randomization).

Two subgroups were identified: those with severe septic shock (requiring norepinephrine in doses of 15 μg/minute or higher) and those with less-severe septic shock (needing norepinephrine in doses of 5 to 14 μg/minute). Patients with unstable coronary artery disease (acute myocardial infarction, angina) and severe congestive heart failure were excluded.

Patients were randomized to receive an intravenous infusion of vasopressin (0.01–0.03 U/minute) or norepinephrine (5–15 mg/minute) in addition to open-labeled vasopressors (excluding vasopressin). The primary outcome was the all-cause mortality rate at 28 days.

Results

At 28 days, fewer patients had died in the vasopressin group than in the norepinephrine group (35.4% vs 39.3%), but the difference was not statistically significant (P = .26). The trend was the same at 90 days (mortality rate 43.9% vs 49.6%, P = .11).

Subgroup analysis showed that in patients with less-severe septic shock, those who received vasopressin had a lower mortality rate at 28 days (26.5% vs 35.7%, P = .05; relative risk 0.74; 95% CI 0.55–1.01) and at 90 days (35.8% vs 46.1%, P = .04; relative risk 0.78, 95% CI 0.61–0.99).

There were no statistically significant differences in any of the other secondary outcomes or in serious adverse events.

Comments

The study has been criticized for several reasons:

• The mean arterial blood pressure at baseline before initiation of vasopressin was 72 mm Hg (and some argue that vasopressin was therefore not needed by the time it was started).
• The time from screening to infusion of the study drug was very long (12 hours).
• The observed mortality rate was lower than expected (37%).

Despite these considerations, the VASST trial showed that vasopressin is not associated with an increased number of adverse events in patients without active cardiovascular disease. The possible benefit in terms of the mortality rate in the subgroup of patients with less-severe septic shock requires further investigation.

Is dopamine equivalent to norepinephrine?

Previously, the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a multicenter, observational cohort study, found that dopamine use was associated with a higher all-cause mortality rate in the ICU compared with no dopamine.²⁵ This finding had not been reproduced, as few well-designed studies had compared the effects of dopamine and norepinephrine.

The SOAP II study

DE BACKER D, BISTON P, DEVRIENDT J, ET AL; SOAP II INVESTIGATORS.. COMPARISON OF DOPAMINE AND NOREPINEPHRINE IN THE TREATMENT OF SHOCK. N ENGL J MED 2010; 362:779–789.

The SOAP II study,²⁶ a multicenter, randomized trial, compared dopamine vs norepinephrine as first-line vasopressor therapy. In patients with refractory shock despite use of dopamine 20 μg/kg/minute or norepinephrine 0.19 μg/kg/minute, open-label norepinephrine, epinephrine, or vasopressin was added.

The primary outcome was the mortality rate at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events.

Results

A total of 1,679 patients were included; 858 were assigned to dopamine and 821 to norepinephrine. Most (1,044, 62%) of the patients had a diagnosis of septic shock.

No significant difference in mortality rates was noted at 28 days: 52.5% with dopamine vs 48.5% with norepinephrine (P = .10).

However, there were more arrhythmias in the patients treated with dopamine: 207 events (24.1%) vs 102 events (12.4%) (P < .001). The number of other adverse events such as renal failure, myocardial infarction, arterial occlusion, or skin necrosis was not different between the groups.

A subgroup analysis showed that dopamine was associated with more deaths at 28 days in patients with cardiogenic shock (P = .03) but not in patients with septic shock (P = .19) or with hypovolemic shock (P = .84).

Comments

The study was criticized because the patients may not have received adequate fluid resuscitation (the study considered adequate resuscitation to be equivalent to 1 L of crystalloids or 500 mL of colloids), as different degrees of volume depletion among patients make direct comparisons of vasopressor effects difficult.

Additionally, the study defined dopamine 20 μg/kg/minute as being equipotent with norepinephrine 0.19 μg/kg/minute. Comparisons of potency between drugs are difficult to establish, as there are no available data.

Nevertheless, this study further confirms previous findings suggesting that norepinephrine is not associated with more end-organ damage (such as renal failure or skin ischemia), and shows that dopamine may increase the number of adverse events, particularly in patients with cardiac disease.

We have seen significant growth in clinical research in critical care medicine in the last decade. Advances have been made in many important areas in this field; of these, advances in treating septic shock and acute respiratory distress syndrome (ARDS), and also in supportive therapies for critically ill patients (eg, sedatives, insulin), have perhaps received the most attention.

Of note, several once-established therapies in these areas have failed the test of time, as the result of evidence from more-recent clinical trials. For example, recent studies have shown that a pulmonary arterial catheter does not improve outcomes in patients with ARDS. Similarly, what used to be “optimal” fluid management in patients with ARDS is no longer considered appropriate.

In this review, we summarize eight major studies in critical care medicine published in the last 5 years, studies that have contributed to changes in our practice in the intensive care unit (ICU).

FLUID MANAGEMENT IN ARDS

Key points

• In patients with acute lung injury (ALI) and ARDS, fluid restriction is associated with better outcomes than a liberal fluid policy.
• A pulmonary arterial catheter is not necessary and, compared with a central venous catheter, may result in more complications in patients with ALI and ARDS.

Background

Fluid management practices in patients with ARDS have been extremely variable. Two different approaches are commonly used: the liberal or “wet” approach to optimize tissue perfusion and the “dry” approach, which focuses on reducing lung edema. Given that most deaths attributed to ARDS result from extrapulmonary organ failure, aggressive fluid restriction has been the less popular approach.

Additionally, although earlier studies and meta-analyses suggested that the use of a pulmonary arterial catheter was not associated with better outcomes in critically ill patients,¹ controversy remained regarding the value of a pulmonary arterial catheter compared with a central venous catheter in guiding fluid management in patients with ARDS, and data were insufficient to prove one strategy better than the other.

The Fluids and Catheter Treatment Trial (FACTT)

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK; WIEDEMANN HP, WHEELER AP, BERNARD GR, ET AL. COMPARISON OF TWO FLUID-MANAGEMENT STRATEGIES IN ACUTE LUNG INJURY. N ENGL J MED 2006; 354:2564–2575.

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK; WHEELER AP, BERNARD GR, THOMPSON BT, ET AL. PULMONARY-ARTERY VERSUS CENTRAL VENOUS CATHETER TO GUIDE TREATMENT OF ACUTE LUNG INJURY. N ENGL J MED 2006; 354:2213–2224.

The Fluids and Catheter Treatment Trial (FACTT) compared two fluid strategies² and also the utility of a pulmonary arterial catheter vs a central venous catheter³ in patients with ALI or ARDS.

This two-by-two factorial trial randomized 1,000 patients to be treated according to either a conservative (fluid-restrictive or “dry”) or a liberal (“wet”) fluid management strategy for 7 days. Additionally, they were randomly assigned to receive either a central venous catheter or a pulmonary arterial catheter. The trial thus had four treatment groups:

• Fluid-restricted and a central venous catheter, with a goal of keeping the central venous pressure below 4 mm Hg
• Fluid-restricted and a pulmonary arterial catheter: fluids were restricted and diuretics were given to keep the pulmonary artery occlusion pressure below 8 mm Hg
• Fluid-liberal and a central venous catheter: fluids were given to keep the central venous pressure between 10 and 14 mm Hg
• Fluid-liberal and a pulmonary arterial catheter: fluids were given to keep the pulmonary artery occlusion pressure between 14 and 18 mm Hg.

The primary end point was the mortality rate at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and parameters of lung physiology. All patients were managed with a low-tidal-volume strategy.

The ‘dry’ strategy was better

The cumulative fluid balance was −136 mL ± 491 mL in the “dry” group and 6,992 mL ± 502 mL in the “wet” group, a difference of more than 7 L (P < .0001). Of note, before randomization, the patients were already fluid-positive, with a mean total fluid balance of +2,700 mL).²

At 60 days, no statistically significant difference in mortality rate was seen between the fluid-management groups (25.5% in the dry group vs 28.4% in the wet group (P = .30). Nevertheless, patients in the dry group had better oxygenation indices and lung injury scores (including lower plateau airway pressure), resulting in more ventilator-free days (14.6 ± 0.5 vs 12.1 ± 0.5; P = .0002) and ICU-free days (13.4 ± 0.4 vs 11.2 ± 0.4; P = .0003).²

Although those in the dry-strategy group had a slightly lower cardiac index and mean arterial pressure, they did not have a higher incidence of shock.

More importantly, the dry group did not have a higher rate of nonpulmonary organ failure. Serum creatinine and blood urea nitrogen concentrations were slightly higher in this group, but this was not associated with a higher incidence of renal failure or the use of dialysis: 10% in the dry-strategy group vs 14% in the wet-strategy group; P = .0642).²

No advantage with a pulmonary arterial catheter

The mortality rate did not differ between the catheter groups. However, the patients who received a pulmonary arterial catheter stayed in the ICU 0.2 days longer and had twice as many nonfatal cardiac arrhythmias as those who received a central venous catheter.³

Comments

The liberal fluid-strategy group had fluid balances similar to those seen in previous National Institutes of Health ARDS Network trials in which fluid management was not controlled. This suggests that the liberal fluid strategy reflects usual clinical practice.

Although the goals used in this study (central venous pressure < 4 mm Hg or pulmonary artery occlusion pressure < 8 mm Hg) could be difficult to achieve in clinical practice, a conservative strategy of fluid management is preferred in patients with ALI or ARDS, given the benefits observed in this trial.

A pulmonary arterial catheter is not indicated to guide hemodynamic management of patients with ARDS.

 

CORTICOSTEROID USE IN ARDS

Key points

• In selected patients with ARDS, the prolonged use of corticosteroids may result in better oxygenation and a shorter duration of mechanical ventilation.
• Late use of corticosteroids in patients with ARDS (> 14 days after diagnosis) is not indicated and may increase the risk of death.
• The role of corticosteroids in early ARDS (< 7 days after diagnosis) remains controversial.

Background

Systemic corticosteroid therapy was commonly used in ARDS patients in the 1970s and 1980s. However, a single-center study published in the late 1980s showed that a corticosteroid in high doses (methylprednisolone 30 mg/kg) resulted in more complications and was not associated with a lower mortality rate.⁴ On the other hand, a small study that included only patients with persistent ARDS (defined as ARDS lasting for more than 7 days) subsequently showed that oxygenation was significantly better and that fewer patients died while in the hospital with the use of methylprednisolone 2 mg/kg for 32 days.⁵

In view of these divergent findings, the ARDS Network decided to perform a study to help understand the role of corticosteroids in ARDS.

The Late Steroid Rescue Study (LaSRS)

STEINBERG KP, HUDSON LD, GOODMAN RB, ET AL; NATIONAL HEART, LUNG, AND BLOOD INSTITUTE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) CLINICAL TRIALS NETWORK. EFFICACY AND SAFETY OF CORTICOSTEROIDS FOR PERSISTENT ACUTE RESPIRATORY DISTRESS SYNDROME. N ENGL J MED 2006; 354:1671–1684.

The Late Steroid Rescue Study (LaSRS),⁶ a double-blind, multicenter trial, randomly assigned 180 patients with persistent ARDS (defined as ongoing disease 7–28 days after its onset) to receive methylprednisolone or placebo for 21 days.

Methylprednisolone was given in an initial dose of 2 mg/kg of predicted body weight followed by a dose of 0.5 mg/kg every 6 hours for 14 days and then a dose of 0.5 mg/kg every 12 hours for 7 days, and then it was tapered over 2 to 4 days and discontinued. It could be discontinued if 21 days of treatment were completed or if the patient was able to breathe without assistance.

The primary end point was the mortality rate at 60 days. Secondary end points included the number of ventilator-free days, organ-failure-free days, and complications and the levels of biomarkers of inflammation.

No reduction in mortality rates with steroids

The mortality rates did not differ significantly in the corticosteroid group vs the placebo group at 60 days:

• 29.2% with methylprednisolone (95% confidence interval [CI] 20.8–39.4)
• 28.6% with placebo (95% CI 20.3–38.6, P = 1.0).

Mortality rates at 180 days were also similar between the groups:

• 31.5% with methylprednisolone (95% CI 22.8–41.7)
• 31.9% with placebo (95% CI 23.2–42.0, P = 1.0).

In patients randomized between 7 and 13 days after the onset of ARDS, the mortality rates were lower in the methylprednisolone group than in the placebo group but the differences were not statistically significant. The mortality rate in this subgroup was 27% vs 36% (P = .26) at 60 days and was 27% vs 39% (P = .14) at 180 days.

However, in patients randomized more than 14 days after the onset of ARDS, the mortality rate was significantly higher in the methylprednisolone group than in the placebo group at 60 days (35% vs 8%, P = .02) and at 180 days (44% vs 12%, P = .01).

Some benefit in secondary outcomes

At day 28, methylprednisolone was associated with:

• More ventilator-free days (11.2 ± 9.4 vs 6.8 ± 8.5, P < .001)
• More shock-free days (20.7 ± 8.9 vs 17.9 ± 10.2, P = .04)
• More ICU-free days (8.9 ± 8.2 vs 6.7 ± 7.8, P = .02).

Similarly, pulmonary physiologic indices were better with methylprednisolone, specifically:

• The ratio of Pao₂ to the fraction of inspired oxygen at days 3, 4, and 14 (P < .05)
• Plateau pressure at days 4, 5, and 7 (P < .05)
• Static compliance at days 7 and 14 (P < .05).

In terms of side effects, methylprednisolone was associated with more events associated with myopathy or neuropathy (9 vs 0, P = .001), but there were no differences in the number of serious infections or in glycemic control.

Comments

Although other recent studies suggested that corticosteroid use may be associated with a reduction in mortality rates,^7–9 LaSRS did not confirm this effect. Although the doses and length of therapy were similar in these studies, LaSRS was much larger and included patients from the ARDS Network.

Nevertheless, LaSRS was criticized because of strict exclusion criteria and poor enrollment (only 5% of eligible patients were included). Additionally, it was conducted over a period of time when some ICU practices varied significantly (eg, low vs high tidal volume ventilation, tight vs loose glucose control).

The role of corticosteroids in early ARDS (< 7 days after diagnosis) remains controversial at best. Table 1 summarizes recent studies that evaluated the use of corticosteroids in patients with ARDS.

INTERRUPTING SEDATION DURING MECHANICAL VENTILATION

Key points

• Daily awakening of mechanically ventilated patients is safe.
• Daily interruption of sedation in mechanically ventilated patients is associated with a shorter length of mechanical ventilation.

Background

Sedatives are a central component of critical care. Continuous infusions of narcotics, benzodiazepines, and anesthetic agents are frequently used to promote comfort in patients receiving mechanical ventilation.

Despite its widespread use in the ICU, there is little evidence that such sedation improves outcomes. Observational and randomized trials^10–12 have shown that patients who receive continuous infusions of sedatives need to be on mechanical ventilation longer than those who receive intermittent dosing. Additionally, an earlier randomized controlled trial¹³ showed that daily interruption of sedative drug infusions decreased the duration of mechanical ventilation by almost 50% and resulted in a reduction in the length of stay in the ICU.

Despite these findings, many ICU physicians remain skeptical of the value of daily interruption of sedative medications and question the safety of this practice.

The Awakening and Breathing Controlled (ABC) trial

GIRARD TD, KRESS JP, FUCHS BD, ET AL. EFFICACY AND SAFETY OF A PAIRED SEDATION AND VENTILATOR WEANING PROTOCOL FOR MECHANICALLY VENTILATED PATIENTS IN INTENSIVE CARE (AWAKENING AND BREATHING CONTROLLED TRIAL): A RANDOMISED CONTROLLED TRIAL. LANCET 2008; 371:126–134.

The Awakening and Breathing Controlled (ABC) trial¹⁴ was a multicenter, randomized controlled trial that included 336 patients who required at least 12 consecutive hours of mechanical ventilation. All patients had to be receiving patient-targeted sedation.

Those in the intervention group (n = 168) had their sedation interrupted every day, followed by a clinical assessment to determine whether they could be allowed to try breathing spontaneously. The control group (n = 168) also received a clinical assessment for a trial of spontaneous breathing, while their sedation was continued as usual.

In patients in the intervention group who failed the screening for a spontaneous breathing trial, the sedatives were resumed at half the previous dose. Criteria for failure on the spontaneous breathing trial included any of the following: anxiety, agitation, respiratory rate more than 35 breaths per minute for 5 minutes or longer, cardiac arrhythmia, oxygen saturation less than 88% for 5 minutes or longer, or two or more signs of respiratory distress, tachycardia, bradycardia, paradoxical breathing, accessory muscle use, diaphoresis, or marked dyspnea.

 

 

Interrupting sedation was superior

The combination of sedation interruption and a spontaneous breathing trial was superior to a spontaneous breathing trial alone. The mean number of ventilator-free days:

• 14.7 ± 0.9 with sedation interruption
• 11.6 ± 0.9 days with usual care (P = .02).

The median time to ICU discharge:

• 9.1 days with sedation interruption (interquartile range 5.1 to 17.8)
• 12.9 days with usual care (interquartile range 6.0 to 24.2, P = .01).

The mortality rate at 28 days:

• 28% with sedation interruption
• 35% with usual care (P = .21).

The mortality rate at 1 year:

• 44% with sedation interruption
• 58% with usual care (hazard ratio [HR] in the intervention group 0.68, 95% CI 0.50–0.92, P = .01).

Of note, patients in the intervention group had a higher rate of self-extubation (9.6% vs 3.6%, P = .03), but the rate of reintubation was similar between the groups (14% vs 13%, P = .47).

Comments

The addition of daily awakenings to spontaneous breathing trials results in a further reduction in the number of ICU days and increases the number of ventilator-free days.

Of note, the protocol allowed patients in the control group to undergo a spontaneous breathing trial while on sedatives (69% of the patients were receiving sedation at the time). Therefore, a bias effect in favor of the intervention group cannot be excluded. However, both groups had to meet criteria for readiness for spontaneous breathing.

The study demonstrates the safety of daily awakenings and confirms previous findings suggesting that a daily trial of spontaneous breathing results in better ICU outcomes.

GLUCOSE CONTROL IN THE ICU

Key points

• Although earlier studies suggested that intensive insulin therapy might be beneficial in critically ill patients, new findings show that strict glucose control can lead to complications without improving outcomes.

Background

A previous study¹⁵ found that intensive insulin therapy to maintain a blood glucose level between 80 and 110 mg/dL (compared with 180–200 mg/dL) reduced the mortality rate in surgical critical care patients. The mortality rate in the ICU was 4.6% with intensive insulin therapy vs 8.0% with conventional therapy (P < .04), and the effect was more robust for patients who remained longer than 5 days in the ICU (10.6% vs 20.2%).

Importantly, however, hypoglycemia (defined as blood glucose ≤ 40 mg/dL) occurred in 39 patients in the intensive-treatment group vs 6 patients in the conventional-treatment group.

The NICE-SUGAR trial

NICE-SUGAR STUDY INVESTIGATORS; FINFER S, CHITTOCK DR, SU SY, ET AL. INTENSIVE VERSUS CONVENTIONAL GLUCOSE CONTROL IN CRITICALLY ILL PATIENTS. N ENGL J MED 2009; 360:1283–1297.

The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial¹⁶ randomized 6,104 patients in medical and surgical ICUs to receive either intensive glucose control (blood glucose 81–108 mg/dL) with insulin therapy or conventional glucose control (blood glucose < 180 mg/dL). In the conventional-control group, insulin was discontinued if the blood glucose level dropped below 144 mg/dL.

A higher mortality rate with intensive glucose control

As expected, the intensive-control group achieved lower blood glucose levels: 115 vs 144 mg/dL.

Nevertheless, intensive glucose control was associated with a higher incidence of severe hypoglycemia, defined as a blood glucose level lower than 40 mg/dL: 6.8% vs 0.5%.

More importantly, compared with conventional insulin therapy, intensive glucose control was associated with a higher 90-day mortality rate: 27.5% vs 24.9% (odds ratio 1.14, 95% CI 1.02–1.28). These findings were similar in the subgroup of surgical patients (24.4% vs 19.8%, odds ratio 1.31, 95% CI 1.07–1.61).

Comments

Of note, the conventional-control group had more patients who discontinued the treatment protocol prematurely. Additionally, more patients in this group received corticosteroids.

These results widely differ from those of a previous study by van den Berghe et al,¹⁵ which showed that tight glycemic control is associated with a survival benefit. The differences in outcomes are probably largely related to different patient populations, as van den Berghe et al included patients who had undergone cardiac surgery, who were more likely to benefit from strict blood glucose control.

The VISEP trial

BRUNKHORST FM, ENGEL C, BLOOS F, ET AL; GERMAN COMPETENCE NETWORK SEPSIS (SEPNET). INTENSIVE INSULIN THERAPY AND PENTASTARCH RESUSCITATION IN SEVERE SEPSIS. N ENGL J MED 2008; 358:125–139.

The Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial was a multicenter study designed to compare intensive insulin therapy (target blood glucose level 80–110 mg/dL) and conventional glucose control (target blood glucose level 180–200 mg/dL) in patients with severe sepsis.¹⁷ It also compared two fluids for volume resuscitation: 10% pentastarch vs modified Ringer's lactate. It included both medical and surgical patients.

Trial halted early for safety reasons

The mean morning blood glucose level was significantly lower in the intensive insulin group (112 vs 151 mg/dL).

Severe hypoglycemia (blood glucose ≤ 40 mg/dL) was more common in the group that received intensive insulin therapy (17% vs 4.1%, P < .001).

Mortality rates at 28 days did not differ significantly: 24.7% with intensive control vs 26.0% with conventional glucose control. The mortality rate at 90 days was 39.7% in the intensive therapy group and 35.4% in the conventional therapy group, but the difference was not statistically significant.

The intensive insulin arm of the trial was stopped after 488 patients were enrolled because of a higher rate of hypoglycemia (12.1% vs 2.1%) and of serious adverse events (10.9% vs 5.2%).

Additionally, the fluid resuscitation arm of the study was suspended at the first planned interim analysis because of a higher risk of organ failure in the 10% pentastarch group.

 

CORTICOSTEROID THERAPY IN SEPTIC SHOCK

Key points

• Corticosteroid therapy improves hemodynamic outcomes in patients with severe septic shock.
• Although meta-analyses suggest the mortality rate is lower with corticosteroid therapy, there is not enough evidence from randomized controlled trials to prove that the use of low-dose corticosteroids lowers the mortality rate in patients with septic shock.
• The corticotropin (ACTH) stimulation test should not be used to determine the need for corticosteroids in patients with septic shock.

Background

A previous multicenter study,¹⁸ performed in France, found that the use of corticosteroids in patients with septic shock resulted in lower rates of death at 28 days, in the ICU, and in the hospital and a shorter time to vasopressor withdrawal. Nevertheless, the beneficial effects were not observed in patients with adequate adrenal reserve (based on an ACTH stimulation test).

This study was criticized because of a high mortality rate in the placebo group.

The CORTICUS study

SPRUNG CL, ANNANE D, KEH D, ET AL; CORTICUS STUDY GROUP. HYDROCORTISONE THERAPY FOR PATIENTS WITH SEPTIC SHOCK. N ENGL J MED 2008; 358:111–124.

The Corticosteroid Therapy of Septic Shock (CORTICUS) study was a multicenter trial that randomly assigned 499 patients with septic shock to receive hydrocortisone (50 mg intravenously every 6 hours for 5 days, followed by a 6-day taper period) or placebo.¹⁹

Patients were eligible to be enrolled within 72 hours of onset of shock. Similar to previous studies, the CORTICUS trial classified patients on the basis of an ACTH stimulation test as having inadequate adrenal reserve (a cortisol increase of ≤ 9 μg/dL) or adequate adrenal reserve (a cortisol increase of > 9 μg/dL).

Faster reversal of shock with steroids

At baseline, the mean Simplified Acute Physiologic Score II (SAPS II) was 49 (the range of possible scores is 0 to 163; the higher the score the worse the organ dysfunction).

Hydrocortisone use resulted in a shorter duration of vasopressor use and a faster reversal of shock (3.3 days vs 5.8 days, P < .001).

This association was the same when patients were divided according to response to ACTH stimulation test. Time to reversal of shock in responders:

• 2.8 days with hydrocortisone
• 5.8 days with placebo (P < .001).

Time to reversal of shock in nonresponders:

• 3.9 days with hydrocortisone
• 6.0 days with placebo (P = .06).

Nevertheless, the treatment did not reduce the mortality rate at 28 days overall (34.3% vs 31.5% P = .51), or in the subgroups based on response to ACTH, or at any other time point. A post hoc analysis suggested that patients who had a systolic blood pressure of less than 90 mm Hg within 30 minutes of enrollment had a greater benefit in terms of mortality rate, but the effect was not statistically significant: the absolute difference was −11.2% (P = 0.28). Similarly, post hoc analyses also revealed a higher rate of death at 28 days in patients who received etomidate (Amidate) before randomization in both groups (P = .03).

Importantly, patients who received corticosteroids had a higher incidence of superinfections, including new episodes of sepsis or septic shock, with a combined odds ratio of 1.37 (95% CI 1.05–1.79).

Length of stay in the hospital or in the ICU was similar in patients who received corticosteroids and in those who received placebo. The ICU length of stay was 19 ± 31 days with hydrocortisone vs 18 ± 17 days with placebo (P = .51).

Comments

The CORTICUS trial showed that low-dose corticosteroid therapy results in faster reversal of shock in patients with severe septic shock. The hemodynamic benefits are present in all patients regardless of response to the ACTH stimulation test.

Nevertheless, contrary to previous findings,¹⁸ corticosteroid use was not associated with an improvement in mortality rates. Important differences exist between these two studies:

• The mortality rates in the placebo groups were significantly different (> 50% in the French study vs 30% in CORTICUS).
• The SAPS II scores were different in these two trials (55 vs 49), suggesting a greater severity of illness in the French study.
• The criteria for enrollment were different: the French study included patients who had a systolic blood pressure lower than 90 mm Hg for more than 1 hour despite fluid administration and vasopressor use, whereas the CORTICUS trial included patients who had a systolic blood pressure lower than 90 mm Hg for more than 1 hour despite fluid administration or vasopressor use.
• The time of enrollment was different: patients were enrolled much faster in the French study (within 8 hours) than in the CORTICUS trial (within 72 hours).

A recent meta-analysis of 17 randomized trials (including the CORTICUS study), found that, compared with those who received placebo, patients who received corticosteroids had a small reduction in the 28-day mortality rate (HR 0.84, 95% CI 0.71–1.00, P < .05).²⁰ Of note, this meta-analysis has been criticized for possible publication bias and also for a large degree of heterogeneity in its results.²¹

 

VASOPRESSOR THERAPY IN SHOCK

Key points

• Vasopressin use in patients with severe septic shock is not associated with an improvement in mortality rates.
• Vasopressin should not be used as a first-line agent in patients with septic shock.
• Norepinephrine should be considered a first-line agent in patients with shock.
• Compared with norepinephrine, the use of dopamine in patients with shock is associated with similar mortality rates, although its use may result in a greater number of cardiac adverse events.

Background

Vasopressin gained popularity in critical care in the last 10 years because several small studies showed that adding it improves hemodynamics and results in a reduction in the doses of catecholamines in patients with refractory septic shock.²² Furthermore, the Surviving Sepsis Campaign guidelines recommended the use of vasopressin in patients who have refractory shock despite fluid resuscitation and the use of other “conventional” vasopressors.²³

Despite these positive findings, it remained unknown if the use of vasopressin increases the survival rate in patients with septic shock.

The Vasopressin and Septic Shock Trial (VASST)

RUSSELL JA, WALLEY KR, SINGER J, ET AL; VASST INVESTIGATORS. VASOPRESSIN VERSUS NOREPINEPHRINE INFUSION IN PATIENTS WITH SEPTIC SHOCK. N ENGL J MED 2008; 358:877–887.

The Vasopressin and Septic Shock Trial (VASST)²⁴ was a multicenter randomized, double-blind, controlled trial that included 778 patients with refractory septic shock. Refractory shock was defined as the lack of a response to a normal saline fluid bolus of 500 mL or the need for vasopressors (norepinephrine in doses of at least 5 μg/minute or its equivalent for 6 hours or more in the 24 hours before randomization).

Two subgroups were identified: those with severe septic shock (requiring norepinephrine in doses of 15 μg/minute or higher) and those with less-severe septic shock (needing norepinephrine in doses of 5 to 14 μg/minute). Patients with unstable coronary artery disease (acute myocardial infarction, angina) and severe congestive heart failure were excluded.

Patients were randomized to receive an intravenous infusion of vasopressin (0.01–0.03 U/minute) or norepinephrine (5–15 mg/minute) in addition to open-labeled vasopressors (excluding vasopressin). The primary outcome was the all-cause mortality rate at 28 days.

Results

At 28 days, fewer patients had died in the vasopressin group than in the norepinephrine group (35.4% vs 39.3%), but the difference was not statistically significant (P = .26). The trend was the same at 90 days (mortality rate 43.9% vs 49.6%, P = .11).

Subgroup analysis showed that in patients with less-severe septic shock, those who received vasopressin had a lower mortality rate at 28 days (26.5% vs 35.7%, P = .05; relative risk 0.74; 95% CI 0.55–1.01) and at 90 days (35.8% vs 46.1%, P = .04; relative risk 0.78, 95% CI 0.61–0.99).

There were no statistically significant differences in any of the other secondary outcomes or in serious adverse events.

Comments

The study has been criticized for several reasons:

• The mean arterial blood pressure at baseline before initiation of vasopressin was 72 mm Hg (and some argue that vasopressin was therefore not needed by the time it was started).
• The time from screening to infusion of the study drug was very long (12 hours).
• The observed mortality rate was lower than expected (37%).

Despite these considerations, the VASST trial showed that vasopressin is not associated with an increased number of adverse events in patients without active cardiovascular disease. The possible benefit in terms of the mortality rate in the subgroup of patients with less-severe septic shock requires further investigation.

Is dopamine equivalent to norepinephrine?

Previously, the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a multicenter, observational cohort study, found that dopamine use was associated with a higher all-cause mortality rate in the ICU compared with no dopamine.²⁵ This finding had not been reproduced, as few well-designed studies had compared the effects of dopamine and norepinephrine.

The SOAP II study

DE BACKER D, BISTON P, DEVRIENDT J, ET AL; SOAP II INVESTIGATORS.. COMPARISON OF DOPAMINE AND NOREPINEPHRINE IN THE TREATMENT OF SHOCK. N ENGL J MED 2010; 362:779–789.

The SOAP II study,²⁶ a multicenter, randomized trial, compared dopamine vs norepinephrine as first-line vasopressor therapy. In patients with refractory shock despite use of dopamine 20 μg/kg/minute or norepinephrine 0.19 μg/kg/minute, open-label norepinephrine, epinephrine, or vasopressin was added.

The primary outcome was the mortality rate at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events.

Results

A total of 1,679 patients were included; 858 were assigned to dopamine and 821 to norepinephrine. Most (1,044, 62%) of the patients had a diagnosis of septic shock.

No significant difference in mortality rates was noted at 28 days: 52.5% with dopamine vs 48.5% with norepinephrine (P = .10).

However, there were more arrhythmias in the patients treated with dopamine: 207 events (24.1%) vs 102 events (12.4%) (P < .001). The number of other adverse events such as renal failure, myocardial infarction, arterial occlusion, or skin necrosis was not different between the groups.

A subgroup analysis showed that dopamine was associated with more deaths at 28 days in patients with cardiogenic shock (P = .03) but not in patients with septic shock (P = .19) or with hypovolemic shock (P = .84).

Comments

The study was criticized because the patients may not have received adequate fluid resuscitation (the study considered adequate resuscitation to be equivalent to 1 L of crystalloids or 500 mL of colloids), as different degrees of volume depletion among patients make direct comparisons of vasopressor effects difficult.

Additionally, the study defined dopamine 20 μg/kg/minute as being equipotent with norepinephrine 0.19 μg/kg/minute. Comparisons of potency between drugs are difficult to establish, as there are no available data.

Nevertheless, this study further confirms previous findings suggesting that norepinephrine is not associated with more end-organ damage (such as renal failure or skin ischemia), and shows that dopamine may increase the number of adverse events, particularly in patients with cardiac disease.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

Recently, a number of new oral and parenteral anticoagulants have been developed (Table 1) with the aim of overcoming some of the drawbacks of warfarin and the other currently available agents, and to improve the prevention and treatment of thromboembolic disorders.

DABIGATRAN, A THROMBIN INHIBITOR

Dabigatran, developed by Boehringer Ingelheim, is a potent, competitive, and reversible inhibitor of both free and clot-bound thrombin, inhibiting both thrombin activity and generation (Table 2).^17,18

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

 

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

Dabigatran has been evaluated in a number of trials for its ability to prevent ischemic stroke and systemic embolization in patients with atrial fibrillation and to prevent and treat venous thromboembolism in surgical orthopedic patients, and in patients with acute coronary syndrome (Table 3).^{1–4,22–25}

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

In addition to its pharmacologic advantages, dabigatran demonstrated two other major advantages over warfarin in the RE-LY trial in patients with atrial fibrillation (Table 4). First, the rate of intracranial bleeding, a major devastating complication of warfarin, was 60% lower with dabigatran 150 mg twice a day than with warfarin—and lower still with dabigatran 110 mg twice a day.¹ Second, the rate of stroke or systemic embolism was 34% lower in the group that got dabigatran 150 mg twice a day than in the group that got warfarin.

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

 

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

Recently, a number of new oral and parenteral anticoagulants have been developed (Table 1) with the aim of overcoming some of the drawbacks of warfarin and the other currently available agents, and to improve the prevention and treatment of thromboembolic disorders.

DABIGATRAN, A THROMBIN INHIBITOR

Dabigatran, developed by Boehringer Ingelheim, is a potent, competitive, and reversible inhibitor of both free and clot-bound thrombin, inhibiting both thrombin activity and generation (Table 2).^17,18

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

 

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

Dabigatran has been evaluated in a number of trials for its ability to prevent ischemic stroke and systemic embolization in patients with atrial fibrillation and to prevent and treat venous thromboembolism in surgical orthopedic patients, and in patients with acute coronary syndrome (Table 3).^{1–4,22–25}

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

In addition to its pharmacologic advantages, dabigatran demonstrated two other major advantages over warfarin in the RE-LY trial in patients with atrial fibrillation (Table 4). First, the rate of intracranial bleeding, a major devastating complication of warfarin, was 60% lower with dabigatran 150 mg twice a day than with warfarin—and lower still with dabigatran 110 mg twice a day.¹ Second, the rate of stroke or systemic embolism was 34% lower in the group that got dabigatran 150 mg twice a day than in the group that got warfarin.

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

 

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

Recently, a number of new oral and parenteral anticoagulants have been developed (Table 1) with the aim of overcoming some of the drawbacks of warfarin and the other currently available agents, and to improve the prevention and treatment of thromboembolic disorders.

DABIGATRAN, A THROMBIN INHIBITOR

Dabigatran, developed by Boehringer Ingelheim, is a potent, competitive, and reversible inhibitor of both free and clot-bound thrombin, inhibiting both thrombin activity and generation (Table 2).^17,18

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

 

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

Dabigatran has been evaluated in a number of trials for its ability to prevent ischemic stroke and systemic embolization in patients with atrial fibrillation and to prevent and treat venous thromboembolism in surgical orthopedic patients, and in patients with acute coronary syndrome (Table 3).^{1–4,22–25}

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

In addition to its pharmacologic advantages, dabigatran demonstrated two other major advantages over warfarin in the RE-LY trial in patients with atrial fibrillation (Table 4). First, the rate of intracranial bleeding, a major devastating complication of warfarin, was 60% lower with dabigatran 150 mg twice a day than with warfarin—and lower still with dabigatran 110 mg twice a day.¹ Second, the rate of stroke or systemic embolism was 34% lower in the group that got dabigatran 150 mg twice a day than in the group that got warfarin.

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

 

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Popular questionnaires to screen for alcohol misuse include the CAGE, the TWEAK, and the short form of the Alcohol Use Disorder Identification Test (AUDIT-C). Any of these is recommended. The important thing is to be proactive about screening for this very common and underrecognized problem.

A COMMON PROBLEM, NOT OFTEN ADMITTED

Alcohol use disorder, which ranges from hazardous drinking to binge drinking and alcohol dependence, is more common than admitted and often goes undiagnosed. Its personal, societal, and economic consequences cannot be overemphasized. Alcohol use is responsible for 85,000 deaths each year in the United States, and it is linked to substantial medical and psychiatric consequences and injuries, especially motor vehicle accidents. The estimated annual cost of problems attributed to alcohol use is over $185 billion.¹

About three in 10 US adults drink at levels that increase their risk for alcohol-related consequences, and about one in four adults currently abuses alcohol or is dependent on it.² In 2009, 6.8% of the US population age 12 and above reported heavy drinking, with highest rates in those ages 21 to 29.³ The rate of alcohol use was higher in men than in women, but about 10% of pregnant women ages 15 to 44 reported current alcohol use.³

The prevalence of alcohol use disorder ranges from 2% to 29% in a typical ambulatory primary care medical practice.⁴ And only one-third of people with alcohol use disorder are diagnosed.

Studies and experience have shown that problem drinkers tend to not seek help until they have advanced dependence, often with associated medical and sociolegal complications. It is also well established that the earlier the diagnosis is made and appropriate intervention is offered, the better the prognosis.

WHAT IS THE GOAL OF SCREENING?

The goals of screening for alcohol use disorder are to estimate the patient’s risk level, to identify those at risk because they exceed defined limits, and to identify those with evidence of an active problem, ie, with adverse consequences related to their drinking. This screening paves the way for further assessment, definitive diagnosis, and a treatment plan.

The US Preventive Services Task Force recommends screening and behavioral counseling interventions (such as a brief intervention) in the primary care setting to reduce alcohol misuse by adults, including pregnant women.⁵ In addition, most primary care patients who screen positive for heavy drinking or alcohol use disorder show motivation and readiness to change, and those with the most severe symptoms tend to be the most ready.⁶

THE IDEAL QUESTIONNAIRE: SENSITIVE, SPECIFIC, AND SHORT

The ideal alcohol screening questionnaire for a busy practice should be brief and highly sensitive and specific for identifying the spectrum of alcohol misuse. Also, it should be easy to recall so it can be part of routine face-to-face discussion with the patient during an office visit.

Further, it should include questions that focus on the consequences of drinking as well as on quantity and frequency. It should also take into account factors such as the patient’s age, sex, race or ethnicity, and pregnancy status, as these can influence the effectiveness of the screening method.

Problems with focusing on quantity alone

“Risky use” is defined (in a non-alcohol-dependent person or one with no alcohol-related consequences) as more than seven standard drinks per week or more than three per occasion for women, and more than 14 standard drinks per week or more than four per occasion for men.²

A standard drink in the United States contains about 12 to 14 g of ethanol: a 12-oz can or bottle of beer, a 5-oz glass of wine, or about 1.5 oz of 80-proof liquor.²

The common single-item screening test asks, “How many times in the past year have you had more than four drinks (for women) or five drinks (for men) in a day?” This is recommended by the National Institute on Alcohol Abuse and Alcoholism for brief screening in primary care. However, a positive answer (ie, one or more times in the past year) has a sensitivity of only 82% and a specificity of only 79% for detecting unhealthy alcohol use, and an even lower specificity (67%) for detecting current alcohol use disorder.⁷

The CAGE questionnaire

The four-item CAGE questionnaire⁸ focuses on the consequences of drinking:

• C: Have you felt the need to cut down on your drinking?
• A: Have you ever felt annoyed by someone criticizing your drinking?
• G: Have you ever felt bad or guilty about your drinking?
• E: Have you ever had an eye-opener—a drink the first thing in the morning to steady your nerves?

A yes to one or more of the questions denotes a need for further assessment.

The CAGE questionnaire is simple, non-threatening, brief, and easy to remember. A yes answer to two or more items has a sensitivity of 75% to 95% and a specificity of 84% to 97% for alcohol dependence.⁹ However, CAGE is less sensitive for identifying nonalcohol-dependent at-risk drinkers. The patient’s sex and ethnicity have also been found to affect its performance somewhat, with some studies showing a sensitivity as low as 50% in adult white women and as low as 40% in at-risk groups ages 60 and over.

 

 

The TWEAK questionnaire

The TWEAK is a modification of the CAGE and includes a question about tolerance; it has a sensitivity of 87% for harmful drinking and 84% for dependence, especially in trauma-related cases.⁹ It has also been found to be better than the CAGE for screening pregnant patients.

• Tolerance: How many drinks can you hold without falling asleep or passing out? (2 points if six drinks or more)
• Worried: Have friends or relatives worried about your drinking? (2 points if yes)
• Eye-opener: Do you sometimes take a drink in the morning when you first get up? (1 point if yes)
• Amnesia: Have friends or relatives told you about things you said or did while drinking that you could not remember? (1 point if yes)
• Cut down: Do you sometimes feel the need to cut down on your drinking? (1 point if yes)

An answer of ≥ 6 to the first question or a total score of 3 or more denotes a problem with alcohol use and a need for further assessment.¹⁰

The AUDIT-C

The AUDIT-C, a shorter form of the 10-item AUDIT developed by the World Health Organization, uses only the first three questions of the full-length AUDIT. The three-item AUDIT-C has a sensitivity ranging from 85% in Hispanic women to 95% in white men.^9,11 The questions center on the quantity and frequency of alcohol use:

• How often do you have a drink containing alcohol? Answer choices: never; monthly or less often; 2 to 4 times a month; 2 to 3 times a week; 4 or more times a week.
• How many standard drinks containing alcohol do you have on a typical day when you are drinking? Answer choices: one or two; three or four; five or six; seven to nine; 10 or more.
• How often do you have six or more drinks on one occasion? Answer choices: never, less than monthly; monthly; weekly; daily or almost.

Scoring is 0 for never, and 1, 2, 3, or 4 for the subsequent answer choices in each question.

The cut-off score for the AUDIT-C is usually a total of 3 points for women and 4 for men: ie, a score of 3 or higher for women and a score of 4 or higher for men indicate alcohol use disorder and the need for further assessment.

The AUDIT questionnaire has been found not only to have a high sensitivity (83%) and specificity (90%) for identifying alcohol dependence, but also to be more sensitive than the CAGE questionnaire (85% vs 75%) for identifying harmful drinking, hazardous drinking, and at-risk drinking. (Note: The full version of AUDIT performed similarly to the three-item AUDIT-C for detecting heavy drinking and active abuse or dependence.¹²) Furthermore, it has performed well as a screening test in many multinational trials of alcohol brief intervention. The questions about quantity of alcohol consumed may be even more suitable for adolescents and young adults, who tend to fall into the harmful-hazardous drinking category rather than the dependent category. In some studies, patients tended to reveal less with the CAGE questionnaire when it was preceded by direct and close-ended questions about the quantity and frequency of alcohol use, thus reducing its sensitivity.¹³

The AUDIT and TWEAK questionnaires showed greater sensitivity in both men and women than the CAGE questionnaire and were equally sensitive in African Americans.¹⁴

HOW TO FIT ALCOHOL SCREENING INTO AN OFFICE VISIT

A practical way to fit alcohol screening into an office visit is to include a questionnaire in the assessment papers completed by the patient while in the waiting room. In other settings, these questions may be asked by trained nursing staff as part of the initial assessment, ie, while obtaining the patient’s weight and vital statistics. This can be briefly reviewed by the physician during the face-to-face history and physical examination.

A concerted effort is needed to proactively screen for alcohol use. A combination of questions about the effect, the quantity, and the frequency of alcohol use is the best way to screen for the many different aspects of alcohol use disorder—many of which can be managed in the primary care setting through brief interventions without referral to a specialist.

When screening for alcohol misuse, it is also important to consider factors such as age, sex, race or ethnicity, pregnancy, and history of recent trauma or surgery.

Popular questionnaires to screen for alcohol misuse include the CAGE, the TWEAK, and the short form of the Alcohol Use Disorder Identification Test (AUDIT-C). Any of these is recommended. The important thing is to be proactive about screening for this very common and underrecognized problem.

A COMMON PROBLEM, NOT OFTEN ADMITTED

Alcohol use disorder, which ranges from hazardous drinking to binge drinking and alcohol dependence, is more common than admitted and often goes undiagnosed. Its personal, societal, and economic consequences cannot be overemphasized. Alcohol use is responsible for 85,000 deaths each year in the United States, and it is linked to substantial medical and psychiatric consequences and injuries, especially motor vehicle accidents. The estimated annual cost of problems attributed to alcohol use is over $185 billion.¹

About three in 10 US adults drink at levels that increase their risk for alcohol-related consequences, and about one in four adults currently abuses alcohol or is dependent on it.² In 2009, 6.8% of the US population age 12 and above reported heavy drinking, with highest rates in those ages 21 to 29.³ The rate of alcohol use was higher in men than in women, but about 10% of pregnant women ages 15 to 44 reported current alcohol use.³

The prevalence of alcohol use disorder ranges from 2% to 29% in a typical ambulatory primary care medical practice.⁴ And only one-third of people with alcohol use disorder are diagnosed.

Studies and experience have shown that problem drinkers tend to not seek help until they have advanced dependence, often with associated medical and sociolegal complications. It is also well established that the earlier the diagnosis is made and appropriate intervention is offered, the better the prognosis.

WHAT IS THE GOAL OF SCREENING?

The goals of screening for alcohol use disorder are to estimate the patient’s risk level, to identify those at risk because they exceed defined limits, and to identify those with evidence of an active problem, ie, with adverse consequences related to their drinking. This screening paves the way for further assessment, definitive diagnosis, and a treatment plan.

The US Preventive Services Task Force recommends screening and behavioral counseling interventions (such as a brief intervention) in the primary care setting to reduce alcohol misuse by adults, including pregnant women.⁵ In addition, most primary care patients who screen positive for heavy drinking or alcohol use disorder show motivation and readiness to change, and those with the most severe symptoms tend to be the most ready.⁶

THE IDEAL QUESTIONNAIRE: SENSITIVE, SPECIFIC, AND SHORT

The ideal alcohol screening questionnaire for a busy practice should be brief and highly sensitive and specific for identifying the spectrum of alcohol misuse. Also, it should be easy to recall so it can be part of routine face-to-face discussion with the patient during an office visit.

Further, it should include questions that focus on the consequences of drinking as well as on quantity and frequency. It should also take into account factors such as the patient’s age, sex, race or ethnicity, and pregnancy status, as these can influence the effectiveness of the screening method.

Problems with focusing on quantity alone

“Risky use” is defined (in a non-alcohol-dependent person or one with no alcohol-related consequences) as more than seven standard drinks per week or more than three per occasion for women, and more than 14 standard drinks per week or more than four per occasion for men.²

A standard drink in the United States contains about 12 to 14 g of ethanol: a 12-oz can or bottle of beer, a 5-oz glass of wine, or about 1.5 oz of 80-proof liquor.²

The common single-item screening test asks, “How many times in the past year have you had more than four drinks (for women) or five drinks (for men) in a day?” This is recommended by the National Institute on Alcohol Abuse and Alcoholism for brief screening in primary care. However, a positive answer (ie, one or more times in the past year) has a sensitivity of only 82% and a specificity of only 79% for detecting unhealthy alcohol use, and an even lower specificity (67%) for detecting current alcohol use disorder.⁷

The CAGE questionnaire

The four-item CAGE questionnaire⁸ focuses on the consequences of drinking:

• C: Have you felt the need to cut down on your drinking?
• A: Have you ever felt annoyed by someone criticizing your drinking?
• G: Have you ever felt bad or guilty about your drinking?
• E: Have you ever had an eye-opener—a drink the first thing in the morning to steady your nerves?

A yes to one or more of the questions denotes a need for further assessment.

The CAGE questionnaire is simple, non-threatening, brief, and easy to remember. A yes answer to two or more items has a sensitivity of 75% to 95% and a specificity of 84% to 97% for alcohol dependence.⁹ However, CAGE is less sensitive for identifying nonalcohol-dependent at-risk drinkers. The patient’s sex and ethnicity have also been found to affect its performance somewhat, with some studies showing a sensitivity as low as 50% in adult white women and as low as 40% in at-risk groups ages 60 and over.

 

 

The TWEAK questionnaire

The TWEAK is a modification of the CAGE and includes a question about tolerance; it has a sensitivity of 87% for harmful drinking and 84% for dependence, especially in trauma-related cases.⁹ It has also been found to be better than the CAGE for screening pregnant patients.

• Tolerance: How many drinks can you hold without falling asleep or passing out? (2 points if six drinks or more)
• Worried: Have friends or relatives worried about your drinking? (2 points if yes)
• Eye-opener: Do you sometimes take a drink in the morning when you first get up? (1 point if yes)
• Amnesia: Have friends or relatives told you about things you said or did while drinking that you could not remember? (1 point if yes)
• Cut down: Do you sometimes feel the need to cut down on your drinking? (1 point if yes)

An answer of ≥ 6 to the first question or a total score of 3 or more denotes a problem with alcohol use and a need for further assessment.¹⁰

The AUDIT-C

The AUDIT-C, a shorter form of the 10-item AUDIT developed by the World Health Organization, uses only the first three questions of the full-length AUDIT. The three-item AUDIT-C has a sensitivity ranging from 85% in Hispanic women to 95% in white men.^9,11 The questions center on the quantity and frequency of alcohol use:

• How often do you have a drink containing alcohol? Answer choices: never; monthly or less often; 2 to 4 times a month; 2 to 3 times a week; 4 or more times a week.
• How many standard drinks containing alcohol do you have on a typical day when you are drinking? Answer choices: one or two; three or four; five or six; seven to nine; 10 or more.
• How often do you have six or more drinks on one occasion? Answer choices: never, less than monthly; monthly; weekly; daily or almost.

Scoring is 0 for never, and 1, 2, 3, or 4 for the subsequent answer choices in each question.

The cut-off score for the AUDIT-C is usually a total of 3 points for women and 4 for men: ie, a score of 3 or higher for women and a score of 4 or higher for men indicate alcohol use disorder and the need for further assessment.

The AUDIT questionnaire has been found not only to have a high sensitivity (83%) and specificity (90%) for identifying alcohol dependence, but also to be more sensitive than the CAGE questionnaire (85% vs 75%) for identifying harmful drinking, hazardous drinking, and at-risk drinking. (Note: The full version of AUDIT performed similarly to the three-item AUDIT-C for detecting heavy drinking and active abuse or dependence.¹²) Furthermore, it has performed well as a screening test in many multinational trials of alcohol brief intervention. The questions about quantity of alcohol consumed may be even more suitable for adolescents and young adults, who tend to fall into the harmful-hazardous drinking category rather than the dependent category. In some studies, patients tended to reveal less with the CAGE questionnaire when it was preceded by direct and close-ended questions about the quantity and frequency of alcohol use, thus reducing its sensitivity.¹³

The AUDIT and TWEAK questionnaires showed greater sensitivity in both men and women than the CAGE questionnaire and were equally sensitive in African Americans.¹⁴

HOW TO FIT ALCOHOL SCREENING INTO AN OFFICE VISIT

A practical way to fit alcohol screening into an office visit is to include a questionnaire in the assessment papers completed by the patient while in the waiting room. In other settings, these questions may be asked by trained nursing staff as part of the initial assessment, ie, while obtaining the patient’s weight and vital statistics. This can be briefly reviewed by the physician during the face-to-face history and physical examination.

A concerted effort is needed to proactively screen for alcohol use. A combination of questions about the effect, the quantity, and the frequency of alcohol use is the best way to screen for the many different aspects of alcohol use disorder—many of which can be managed in the primary care setting through brief interventions without referral to a specialist.

When screening for alcohol misuse, it is also important to consider factors such as age, sex, race or ethnicity, pregnancy, and history of recent trauma or surgery.

Popular questionnaires to screen for alcohol misuse include the CAGE, the TWEAK, and the short form of the Alcohol Use Disorder Identification Test (AUDIT-C). Any of these is recommended. The important thing is to be proactive about screening for this very common and underrecognized problem.

A COMMON PROBLEM, NOT OFTEN ADMITTED

Alcohol use disorder, which ranges from hazardous drinking to binge drinking and alcohol dependence, is more common than admitted and often goes undiagnosed. Its personal, societal, and economic consequences cannot be overemphasized. Alcohol use is responsible for 85,000 deaths each year in the United States, and it is linked to substantial medical and psychiatric consequences and injuries, especially motor vehicle accidents. The estimated annual cost of problems attributed to alcohol use is over $185 billion.¹

About three in 10 US adults drink at levels that increase their risk for alcohol-related consequences, and about one in four adults currently abuses alcohol or is dependent on it.² In 2009, 6.8% of the US population age 12 and above reported heavy drinking, with highest rates in those ages 21 to 29.³ The rate of alcohol use was higher in men than in women, but about 10% of pregnant women ages 15 to 44 reported current alcohol use.³

The prevalence of alcohol use disorder ranges from 2% to 29% in a typical ambulatory primary care medical practice.⁴ And only one-third of people with alcohol use disorder are diagnosed.

Studies and experience have shown that problem drinkers tend to not seek help until they have advanced dependence, often with associated medical and sociolegal complications. It is also well established that the earlier the diagnosis is made and appropriate intervention is offered, the better the prognosis.

WHAT IS THE GOAL OF SCREENING?

The goals of screening for alcohol use disorder are to estimate the patient’s risk level, to identify those at risk because they exceed defined limits, and to identify those with evidence of an active problem, ie, with adverse consequences related to their drinking. This screening paves the way for further assessment, definitive diagnosis, and a treatment plan.

The US Preventive Services Task Force recommends screening and behavioral counseling interventions (such as a brief intervention) in the primary care setting to reduce alcohol misuse by adults, including pregnant women.⁵ In addition, most primary care patients who screen positive for heavy drinking or alcohol use disorder show motivation and readiness to change, and those with the most severe symptoms tend to be the most ready.⁶

THE IDEAL QUESTIONNAIRE: SENSITIVE, SPECIFIC, AND SHORT

The ideal alcohol screening questionnaire for a busy practice should be brief and highly sensitive and specific for identifying the spectrum of alcohol misuse. Also, it should be easy to recall so it can be part of routine face-to-face discussion with the patient during an office visit.

Further, it should include questions that focus on the consequences of drinking as well as on quantity and frequency. It should also take into account factors such as the patient’s age, sex, race or ethnicity, and pregnancy status, as these can influence the effectiveness of the screening method.

Problems with focusing on quantity alone

“Risky use” is defined (in a non-alcohol-dependent person or one with no alcohol-related consequences) as more than seven standard drinks per week or more than three per occasion for women, and more than 14 standard drinks per week or more than four per occasion for men.²

A standard drink in the United States contains about 12 to 14 g of ethanol: a 12-oz can or bottle of beer, a 5-oz glass of wine, or about 1.5 oz of 80-proof liquor.²

The common single-item screening test asks, “How many times in the past year have you had more than four drinks (for women) or five drinks (for men) in a day?” This is recommended by the National Institute on Alcohol Abuse and Alcoholism for brief screening in primary care. However, a positive answer (ie, one or more times in the past year) has a sensitivity of only 82% and a specificity of only 79% for detecting unhealthy alcohol use, and an even lower specificity (67%) for detecting current alcohol use disorder.⁷

The CAGE questionnaire

The four-item CAGE questionnaire⁸ focuses on the consequences of drinking:

• C: Have you felt the need to cut down on your drinking?
• A: Have you ever felt annoyed by someone criticizing your drinking?
• G: Have you ever felt bad or guilty about your drinking?
• E: Have you ever had an eye-opener—a drink the first thing in the morning to steady your nerves?

A yes to one or more of the questions denotes a need for further assessment.

The CAGE questionnaire is simple, non-threatening, brief, and easy to remember. A yes answer to two or more items has a sensitivity of 75% to 95% and a specificity of 84% to 97% for alcohol dependence.⁹ However, CAGE is less sensitive for identifying nonalcohol-dependent at-risk drinkers. The patient’s sex and ethnicity have also been found to affect its performance somewhat, with some studies showing a sensitivity as low as 50% in adult white women and as low as 40% in at-risk groups ages 60 and over.

 

 

The TWEAK questionnaire

The TWEAK is a modification of the CAGE and includes a question about tolerance; it has a sensitivity of 87% for harmful drinking and 84% for dependence, especially in trauma-related cases.⁹ It has also been found to be better than the CAGE for screening pregnant patients.

• Tolerance: How many drinks can you hold without falling asleep or passing out? (2 points if six drinks or more)
• Worried: Have friends or relatives worried about your drinking? (2 points if yes)
• Eye-opener: Do you sometimes take a drink in the morning when you first get up? (1 point if yes)
• Amnesia: Have friends or relatives told you about things you said or did while drinking that you could not remember? (1 point if yes)
• Cut down: Do you sometimes feel the need to cut down on your drinking? (1 point if yes)

An answer of ≥ 6 to the first question or a total score of 3 or more denotes a problem with alcohol use and a need for further assessment.¹⁰

The AUDIT-C

The AUDIT-C, a shorter form of the 10-item AUDIT developed by the World Health Organization, uses only the first three questions of the full-length AUDIT. The three-item AUDIT-C has a sensitivity ranging from 85% in Hispanic women to 95% in white men.^9,11 The questions center on the quantity and frequency of alcohol use:

• How often do you have a drink containing alcohol? Answer choices: never; monthly or less often; 2 to 4 times a month; 2 to 3 times a week; 4 or more times a week.
• How many standard drinks containing alcohol do you have on a typical day when you are drinking? Answer choices: one or two; three or four; five or six; seven to nine; 10 or more.
• How often do you have six or more drinks on one occasion? Answer choices: never, less than monthly; monthly; weekly; daily or almost.

Scoring is 0 for never, and 1, 2, 3, or 4 for the subsequent answer choices in each question.

The cut-off score for the AUDIT-C is usually a total of 3 points for women and 4 for men: ie, a score of 3 or higher for women and a score of 4 or higher for men indicate alcohol use disorder and the need for further assessment.

The AUDIT questionnaire has been found not only to have a high sensitivity (83%) and specificity (90%) for identifying alcohol dependence, but also to be more sensitive than the CAGE questionnaire (85% vs 75%) for identifying harmful drinking, hazardous drinking, and at-risk drinking. (Note: The full version of AUDIT performed similarly to the three-item AUDIT-C for detecting heavy drinking and active abuse or dependence.¹²) Furthermore, it has performed well as a screening test in many multinational trials of alcohol brief intervention. The questions about quantity of alcohol consumed may be even more suitable for adolescents and young adults, who tend to fall into the harmful-hazardous drinking category rather than the dependent category. In some studies, patients tended to reveal less with the CAGE questionnaire when it was preceded by direct and close-ended questions about the quantity and frequency of alcohol use, thus reducing its sensitivity.¹³

The AUDIT and TWEAK questionnaires showed greater sensitivity in both men and women than the CAGE questionnaire and were equally sensitive in African Americans.¹⁴

HOW TO FIT ALCOHOL SCREENING INTO AN OFFICE VISIT

A practical way to fit alcohol screening into an office visit is to include a questionnaire in the assessment papers completed by the patient while in the waiting room. In other settings, these questions may be asked by trained nursing staff as part of the initial assessment, ie, while obtaining the patient’s weight and vital statistics. This can be briefly reviewed by the physician during the face-to-face history and physical examination.

A concerted effort is needed to proactively screen for alcohol use. A combination of questions about the effect, the quantity, and the frequency of alcohol use is the best way to screen for the many different aspects of alcohol use disorder—many of which can be managed in the primary care setting through brief interventions without referral to a specialist.

When screening for alcohol misuse, it is also important to consider factors such as age, sex, race or ethnicity, pregnancy, and history of recent trauma or surgery.

A 44-year-old woman with end-stage liver disease presents with a painful, ischemic, necrotic lesion on her right lateral and medial thigh (Figure  1). Several months ago, while being evaluated in the hospital for liver transplantation, she developed bacteremia, anion-gap metabolic acidosis, hepatorenal syndrome, and acute renal failure. She began continuous hemodialysis, which lasted for about 1 month, ending 35 days after the renal failure resolved.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions are characteristically erythematous and tender, with mottling of the skin early in the course. As the lesions progress, they develop central necrosis and deep ulcerations with eschar formation. The ulcers have irregular borders and do not heal. Histopathologic study typically shows epidermis with ischemic necrosis and calcium deposition along elastic fibers on Von Kossa calcium stains (Figure 2).

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

A 44-year-old woman with end-stage liver disease presents with a painful, ischemic, necrotic lesion on her right lateral and medial thigh (Figure  1). Several months ago, while being evaluated in the hospital for liver transplantation, she developed bacteremia, anion-gap metabolic acidosis, hepatorenal syndrome, and acute renal failure. She began continuous hemodialysis, which lasted for about 1 month, ending 35 days after the renal failure resolved.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions are characteristically erythematous and tender, with mottling of the skin early in the course. As the lesions progress, they develop central necrosis and deep ulcerations with eschar formation. The ulcers have irregular borders and do not heal. Histopathologic study typically shows epidermis with ischemic necrosis and calcium deposition along elastic fibers on Von Kossa calcium stains (Figure 2).

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

A 44-year-old woman with end-stage liver disease presents with a painful, ischemic, necrotic lesion on her right lateral and medial thigh (Figure  1). Several months ago, while being evaluated in the hospital for liver transplantation, she developed bacteremia, anion-gap metabolic acidosis, hepatorenal syndrome, and acute renal failure. She began continuous hemodialysis, which lasted for about 1 month, ending 35 days after the renal failure resolved.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions are characteristically erythematous and tender, with mottling of the skin early in the course. As the lesions progress, they develop central necrosis and deep ulcerations with eschar formation. The ulcers have irregular borders and do not heal. Histopathologic study typically shows epidermis with ischemic necrosis and calcium deposition along elastic fibers on Von Kossa calcium stains (Figure 2).

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

Few medical emergencies are as dramatic as an acutely rupturing aortic aneurysm. I recall a Thanksgiving in the emergency room about 25 years ago. We were evaluating a man who had suffered a syncopal episode at his holiday dinner table. It was an odd presentation in the ER: hypotension and bradycardia, no inferior myocardial infarction, and no obvious reason to be persistently “vagal.” Initial blood cell counts were normal. He described ill-defined back and then abdominal pain. As the chief surgical resident and I repeated the examination, the patient’s belly became distended, his breath sounds decreased on the left, and within minutes, the surgical team raced him to the operating room.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

Few medical emergencies are as dramatic as an acutely rupturing aortic aneurysm. I recall a Thanksgiving in the emergency room about 25 years ago. We were evaluating a man who had suffered a syncopal episode at his holiday dinner table. It was an odd presentation in the ER: hypotension and bradycardia, no inferior myocardial infarction, and no obvious reason to be persistently “vagal.” Initial blood cell counts were normal. He described ill-defined back and then abdominal pain. As the chief surgical resident and I repeated the examination, the patient’s belly became distended, his breath sounds decreased on the left, and within minutes, the surgical team raced him to the operating room.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

Few medical emergencies are as dramatic as an acutely rupturing aortic aneurysm. I recall a Thanksgiving in the emergency room about 25 years ago. We were evaluating a man who had suffered a syncopal episode at his holiday dinner table. It was an odd presentation in the ER: hypotension and bradycardia, no inferior myocardial infarction, and no obvious reason to be persistently “vagal.” Initial blood cell counts were normal. He described ill-defined back and then abdominal pain. As the chief surgical resident and I repeated the examination, the patient’s belly became distended, his breath sounds decreased on the left, and within minutes, the surgical team raced him to the operating room.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

Several classification schemes are used for aortic dissection and are based on which segment of the aorta is involved (Figure 1).^2,3

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

 

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Many diseases and conditions are associated with aortic dissection (Table 1)^2,3:

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Genetic disorders that lead to aortic aneurysm and dissection include Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysm syndrome, bicuspid aortic valve, Turner syndrome, and vascular Ehlers-Danlos syndrome (Table 2).^2,3,5 Some of these disorders may involve abnormalities in signaling pathways, such as transforming growth factor beta, and others affect aortic smooth muscle cell contractile function.^2,3 Not infrequently, acute aortic dissection may be the inciting event that brings the patient with one of these genetic conditions to initial clinical attention, highlighting the importance of recognizing these disorders.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

 

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

Aortic regurgitation is present in about 40% of patients with acute type A dissection and may be related to one of several mechanisms (Figure 2)^1,2:

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Chest radiography may provide the first clues of aortic dissection. The most frequent findings are a widening of the aortic shadow or mediastinum or an abnormal aortic contour (Figure 3).^2,3 However, radiographic findings are nonspecific and are subject to interobserver variability. Also, importantly, the chest radiograph is normal in 12% to 15% of cases of acute aortic dissection.^1–3

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

 

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

Contrast-enhanced CT is the test most commonly used to diagnose aortic dissection (Figure 4). It is best performed with electrocardiographic gating or multidetector scanning to eliminate pulsation artifacts. The use of intravenous contrast is necessary to visualize the true and false channels; noncontrast studies may miss aortic dissection. CT may also visualize hemopericardium, aortic rupture, and branch vessel involvement.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

TEE has the advantage of being portable, but it requires adequate sedation and skilled personnel. It may define the mechanism of aortic regurgitation in acute dissection, and it may visualize the coronary ostia (Figure 5). Another advantage is that it can ascertain the functioning of the left and right heart. A disadvantage of TEE is that it may not adequately visualize the distal ascending aorta and aortic arch.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

The general recommendations for surgical treatment of acute aortic dissection are listed in Table 3. The goals are to excise the intimal tear, obliterate the false channel by oversewing the aortic edges, and reconstitute the aorta, usually by placing a Dacron interposition graft.

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

 

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

CT shows high-attenuation crescentic or circumferential thickening of the aortic wall on noncontrast studies and low-attenuation thickening on contrast images (Figure 5).^2,3 MRI is also highly accurate in demonstrating intramural hematoma. TEE shows aortic wall thickening with an eccentric aortic lumen and displaced intimal calcification and echolucent spaces in the aortic wall (Figure 6).

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Penetrating atherosclerotic ulcer has a classic appearance on CT, MRI, and TEE, with focal ulceration and a crater-like outpouching (Figure 7). Intramural hemorrhage is often present. These lesions have a high propensity for rupture, and because of the focal nature of these lesions, they are often suitable for endovascular therapy.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

 

 

Genetic evaluation

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

Several classification schemes are used for aortic dissection and are based on which segment of the aorta is involved (Figure 1).^2,3

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

 

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Many diseases and conditions are associated with aortic dissection (Table 1)^2,3:

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Genetic disorders that lead to aortic aneurysm and dissection include Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysm syndrome, bicuspid aortic valve, Turner syndrome, and vascular Ehlers-Danlos syndrome (Table 2).^2,3,5 Some of these disorders may involve abnormalities in signaling pathways, such as transforming growth factor beta, and others affect aortic smooth muscle cell contractile function.^2,3 Not infrequently, acute aortic dissection may be the inciting event that brings the patient with one of these genetic conditions to initial clinical attention, highlighting the importance of recognizing these disorders.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

 

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

Aortic regurgitation is present in about 40% of patients with acute type A dissection and may be related to one of several mechanisms (Figure 2)^1,2:

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Chest radiography may provide the first clues of aortic dissection. The most frequent findings are a widening of the aortic shadow or mediastinum or an abnormal aortic contour (Figure 3).^2,3 However, radiographic findings are nonspecific and are subject to interobserver variability. Also, importantly, the chest radiograph is normal in 12% to 15% of cases of acute aortic dissection.^1–3

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

 

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

Contrast-enhanced CT is the test most commonly used to diagnose aortic dissection (Figure 4). It is best performed with electrocardiographic gating or multidetector scanning to eliminate pulsation artifacts. The use of intravenous contrast is necessary to visualize the true and false channels; noncontrast studies may miss aortic dissection. CT may also visualize hemopericardium, aortic rupture, and branch vessel involvement.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

TEE has the advantage of being portable, but it requires adequate sedation and skilled personnel. It may define the mechanism of aortic regurgitation in acute dissection, and it may visualize the coronary ostia (Figure 5). Another advantage is that it can ascertain the functioning of the left and right heart. A disadvantage of TEE is that it may not adequately visualize the distal ascending aorta and aortic arch.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

The general recommendations for surgical treatment of acute aortic dissection are listed in Table 3. The goals are to excise the intimal tear, obliterate the false channel by oversewing the aortic edges, and reconstitute the aorta, usually by placing a Dacron interposition graft.

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

 

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

CT shows high-attenuation crescentic or circumferential thickening of the aortic wall on noncontrast studies and low-attenuation thickening on contrast images (Figure 5).^2,3 MRI is also highly accurate in demonstrating intramural hematoma. TEE shows aortic wall thickening with an eccentric aortic lumen and displaced intimal calcification and echolucent spaces in the aortic wall (Figure 6).

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Penetrating atherosclerotic ulcer has a classic appearance on CT, MRI, and TEE, with focal ulceration and a crater-like outpouching (Figure 7). Intramural hemorrhage is often present. These lesions have a high propensity for rupture, and because of the focal nature of these lesions, they are often suitable for endovascular therapy.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

 

 

Genetic evaluation

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

Several classification schemes are used for aortic dissection and are based on which segment of the aorta is involved (Figure 1).^2,3

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

 

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Many diseases and conditions are associated with aortic dissection (Table 1)^2,3:

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Genetic disorders that lead to aortic aneurysm and dissection include Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysm syndrome, bicuspid aortic valve, Turner syndrome, and vascular Ehlers-Danlos syndrome (Table 2).^2,3,5 Some of these disorders may involve abnormalities in signaling pathways, such as transforming growth factor beta, and others affect aortic smooth muscle cell contractile function.^2,3 Not infrequently, acute aortic dissection may be the inciting event that brings the patient with one of these genetic conditions to initial clinical attention, highlighting the importance of recognizing these disorders.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

 

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

Aortic regurgitation is present in about 40% of patients with acute type A dissection and may be related to one of several mechanisms (Figure 2)^1,2:

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Chest radiography may provide the first clues of aortic dissection. The most frequent findings are a widening of the aortic shadow or mediastinum or an abnormal aortic contour (Figure 3).^2,3 However, radiographic findings are nonspecific and are subject to interobserver variability. Also, importantly, the chest radiograph is normal in 12% to 15% of cases of acute aortic dissection.^1–3

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

 

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

Contrast-enhanced CT is the test most commonly used to diagnose aortic dissection (Figure 4). It is best performed with electrocardiographic gating or multidetector scanning to eliminate pulsation artifacts. The use of intravenous contrast is necessary to visualize the true and false channels; noncontrast studies may miss aortic dissection. CT may also visualize hemopericardium, aortic rupture, and branch vessel involvement.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

TEE has the advantage of being portable, but it requires adequate sedation and skilled personnel. It may define the mechanism of aortic regurgitation in acute dissection, and it may visualize the coronary ostia (Figure 5). Another advantage is that it can ascertain the functioning of the left and right heart. A disadvantage of TEE is that it may not adequately visualize the distal ascending aorta and aortic arch.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

The general recommendations for surgical treatment of acute aortic dissection are listed in Table 3. The goals are to excise the intimal tear, obliterate the false channel by oversewing the aortic edges, and reconstitute the aorta, usually by placing a Dacron interposition graft.

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

 

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

CT shows high-attenuation crescentic or circumferential thickening of the aortic wall on noncontrast studies and low-attenuation thickening on contrast images (Figure 5).^2,3 MRI is also highly accurate in demonstrating intramural hematoma. TEE shows aortic wall thickening with an eccentric aortic lumen and displaced intimal calcification and echolucent spaces in the aortic wall (Figure 6).

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald&#039;s Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Penetrating atherosclerotic ulcer has a classic appearance on CT, MRI, and TEE, with focal ulceration and a crater-like outpouching (Figure 7). Intramural hemorrhage is often present. These lesions have a high propensity for rupture, and because of the focal nature of these lesions, they are often suitable for endovascular therapy.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

 

 

Genetic evaluation

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.