Over the last 5 years, tremendous attention has focused on endocrine issues
in the ICU. In particular, 3 areas of controversy revolve around the use of
corticosteroids in septic shock, the role for tight blood glucose (BG) control,
and the value of vasopressin infusions. Presently, the Surviving Sepsis
guidelines recommend use of corticosteroids in refractory shock and suggest
tight BG control to be a goal.[1]
Adrenal Pathophysiology in the Critically Ill
Dr. Paul Marik, from Thomas Jefferson University, reviewed adrenal
pathophysiology in critically ill patients. He reminded practitioners that
systemic stress such as sepsis leads to release of cortisol-releasing hormone,
which acts on the pituitary to increase adrenocorticotropic hormone production.
Similarly, cortisol and inflammation are interlinked as tumor necrosis factor
inhibits cortisol secretion. Dr. Marik also noted that differences in both free
and total cortisol are important in sepsis. In general, with stress, the
proportion of cortisol that comprises the free fraction increases.
Unfortunately, measuring free cortisol is difficult and not routinely performed.
Illustrating this principle, Dr. Marik reviewed the findings of Hamrahian and
colleagues.[2] These authors measured total and free cortisol along
with response to cosyntropin stimulation in healthy volunteers and those with
sepsis. They also adjusted for the hypoproteinemia often seen in sepsis, as this
may confound measurements because of its relationship to changes in cortisol
binding protein. Analyzing serum total cortisol levels suggested that critically
ill patients were more often adrenally insufficient. However, review of free
cortisol levels, which removes confounding due to low protein levels, suggested
that many patients had normal adrenal function. In fact, Dr. Marik suggested
that because of this complicated relationship, the term "adrenal insufficiency"
should be abandoned in the ICU. Rather, he proposed the term, "critical illness
related corticosteroid insufficiency" (CIRCI). He defined this as inappropriate
steroid activity given a patient's severity of illness.
Because of complications with the measurement of CIRCI as shown in the report
by Hamrahian and colleagues, Dr. Marik stated that CIRCI is a clinical
diagnosis.[2] He was adamant that it not be based purely on lab
testing. To reinforce his point about issues with lab testing, he presented data
from the Corticosteroid Therapy of Septic Shock (CORTICUS) laboratory
harmonization project. (CORTICUS is discussed below in greater detail). In
CORTICUS, cortisol levels were measured at both local labs and a core lab. In
non-ICU subjects, the correlation between the results from the central lab and
the local labs was high. However, in ICU subjects, the correlation was poor
(R2 = 0.57). He observed that this was likely due to a limitation
with ELISA-based technology and that critically ill persons make antibodies that
interfere with this type of assay. Given the limitations of lab testing, he
suggested that clinicians should consider empiric use of low-dose
corticosteroids in refractory hypotension. He felt this was reasonable given the
absence of any evidence of harm related to the use of corticosteroids. The
results of the study by Annane and colleagues[3] support, to some
extent, the use of corticosteroids in refractory septic shock. However, it seems
premature to draw conclusions regarding harm given that the population they
examined was unique and very severely ill.[3] Dr. Marik concluded his
comments by noting that several professional societies including The Endocrine
Society and the Society for Critical Care Medicine are working on a joint
position statement to hopefully clarify issues related to the administration of
corticosteroids in septic shock.
CORTICUS
While Dr. Marik's presentation dealt with many theoretical aspects of CIRCI
and corticosteroid use in the ICU, Dr. Charles Sprung, of Hadassah Hospital,
presented the actual randomized clinical trial (RCT) results from CORTICUS. He
humorously started by suggesting that utilization of corticosteroids in the ICU
was more a reflection of belief systems than of rigorous clinical trials. It was
this long-term controversy that prompted the need for CORTICUS. Again, reminding
the audience of recent randomized studies of this question, Dr. Sprung outlined
the findings of Annane and colleagues.[3] In persons with refractory
shock begun on glucocorticoids and mineralocorticoids within 8 hours, there was
a mortality benefit in cortrosyn stimulation-challenged "nonresponders." To
confirm and to build on these findings, CORTICUS represented a multicenter,
international, double-blind RCT. The primary end point was 28-day all-cause
mortality in "nonresponders" (defined as a change of ≤ 9 mcg/dL in cortisol
after a 250-mcg cortrosyn stimulation test). Secondary end points dealt with
mortality in the entire population, organ failure resolution, and safety. The
study was conducted from March 2002 through November 2005 at 52 sites in Europe
and the Middle East. The study was designed to enroll 800 patients so that it
would have sufficient power to detect a 10% difference in mortality. However,
because of difficulty with recruitment, the trial was halted after 500 persons
were enrolled. Inclusion criteria included: evidence of infection along with 2
or more SIRS criteria, shock within the prior 72 hours (defined as systolic
blood pressure < 90 mm Hg or the need for vasopressors), and signs of
hypoperfusion. Patients chronically on corticosteroids, those with advanced
directives, immunosuppressed persons, and moribund subjects were excluded.
Initially, participants were given 50 mg of hydrocortisone every 6 hours for
5 days with a tapering dose over the next 6 days. Fludricortisone was not
administered. The baseline characteristics of the population are shown in the
Table below.
Table. Baseline Characteristics
| Variable |
Corticosteroid Arm |
Placebo |
| Age (years, mean) |
63 |
63 |
| Gender |
67% male |
66% male |
| Medical illness |
32% |
38% |
| Lung as source of infection |
30% |
38% |
| GI source of infection |
49% |
47% |
| Non-responders |
50% |
43% |
GI = gastrointestinal
There were no differences in these baseline characteristics or the severity
of illness between the 2 cohorts. For no outcome end point did there appear to
be a difference with use of corticosteroids. All-cause mortality was similar
between the 2 arms (34% corticosteroids vs 31% placebo). Mortality rates also
did not vary based on responder status. However, nonresponders tended to have
higher mortality overall. Overall, rates of shock reversal appeared better in
those given corticosteroids. This difference was not statistically significant;
however, in the subgroup of responders, time to shock reversal appeared
faster.
With a note of caution, Dr. Sprung reviewed the safety data. Rates of
superinfection were higher in those given corticosteroids (34% vs 27%, P
= .099). The frequency of hospital-acquired new sepsis was also higher in those
randomized to steroids. Hyperglycemia, not surprising, was also more common on
study day 1 in persons treated with corticosteroids.
What explains these findings and why do they differ from earlier trials and
meta-analyses?[4] First, Dr. Sprung suggested that compared with the
report by Annane and colleagues,[3] those in this study were not as
severely ill. The total mortality rate in the Annane trial approached 60% vs 34%
in CORTICUS. Similarly, the allowable duration of shock prior to enrollment was
shorter in the Annane protocol. Relatedly, perhaps there was some difference due
to the withholding of fludricortisone or due to the fact that CORTICUS
encouraged physicians to follow current sepsis guidelines.
Whatever the reason, the findings of CORTICUS give pause to those who have
advocated more frequent use of corticosteroids in septic shock.[4]
Even though it was underpowered, there seems to be no hint of a signal favoring
broader use of corticosteroids. Additionally, there may be an indication of harm
given the data about superinfection. Further analyses are planned and hopefully
these will prove enlightening. Clinicians, nonetheless, must choose if and how
to utilize corticosteroids. Hence, restricting their employment to persons who
resemble those studied by Annane and colleagues might be the most prudent course
as there are clinical trial findings to support this. Broad, routine
administration of corticosteroids in severe sepsis and shock seems unwarranted
at present.
Insulin Therapy
Dr. Steven Pastores, from Memorial Sloan-Kettering Cancer Institute in New
York, reviewed the literature regarding intensive insulin therapy in the ICU.
Hyperglycemia has been correlated with adverse outcomes in multiple disease
states ranging from acute myocardial infarction to traumatic brain injury.
Additionally, hyperglycemia in the ICU is a common problem. Historically, we
have ignored BG unless it surpasses 200 mg/dL. This, though, he commented, can
no longer be accepted.
There are multiple mechanisms for hyperglycemia in critically ill patients
that range from increased glycolysis to enhanced insulin resistance. Moreover,
cortisol and cytokines are both elevated in severe sepsis and other conditions
encountered in the ICU, and they promote gluconeogenesis. The initial RCT that
prompted interest in tight blood sugar control was reported several years ago by
Van den Berghe and colleagues.[5] In this trial of over 1500 surgical
ICU patients, subjects were randomized to intensive insulin therapy to maintain
BG in the 80-110 mg/dL range vs a more liberal approach tolerating BG levels of
up to 200 mg/dL. Both ICU and hospital mortality were substantially reduced as a
result of this. The benefit of tight BG control was most evident in those who
stayed for > 5 days in the ICU. Multiple beneficial secondary effects of
tighter control were reported and included decreases in blood stream infections,
transfusions, and acute renal failure. Severe hypoglycemia was more common with
the stricter insulin regimen, but this did not appear to result in clinical
harm.
In a second effectiveness analysis, Krinsley confirmed the findings of Van
den Berghe.[6] In his 1600-patient before/after study, hospital
mortality was substantially reduced with stricter BG control. Similarly,
transfusion use and rates of acute renal failure fell with better control of
BG.
Why is this protocolized approach to BG control effective? One possibility is
that it may not be related to BG control itself but may be a consequence of
increased utilization of insulin. As a hormone, insulin has many properties
other than purely the regulation of BG. For example, insulin has
anti-inflammatory properties and alters endothelial function. Finney and
coworkers,[7] according to Dr. Pastores, examined this issue. After
controlling for both extent of hyperglycemia and degree of insulin administered,
they noted that the benefits all appeared directly related to the degree of BG
control independent of the dose of insulin needed to achieve that control.
Confusing the approach to tight BG control, Dr. Pastores said, are the more
recent findings from a follow-up study by Van den Berge and
colleagues[8] that dealt exclusively with medically ill patients.
Using a protocol similar to their surgical ICU study, these authors randomized
1200 medical ICU patients. Persons expected to stay in the ICU > 3 days were
their predominant focus. Overall, there was no difference in survival in this
trial. However, in those who did in fact stay in the ICU > 3 days, mortality
fell. This, though, was at the expense of higher mortality in persons with
shorter ICU stays. Because of the lack of blinding and imbalances in the
populations, interpretation of these results is difficult. Some suggest that the
potential for harm in those with shorter ICU stays should preclude broad
adoption of tight BG control protocols in ICUs, while others state that those
who died early may have been "destined" to die.
Dr. Pastores noted that several subsequent studies of BG control in the ICU
further complicate matters as they suggest that intensive insulin therapy may be
associated with clear harm. Presented earlier this year, per him, were the
findings from Efficacy of Volume Substitution and Insulin Therapy in Severe
Sepsis (VISEP trial), a European study of colloids vs crystalloids. Intensive
insulin therapy was studied within this trial. Severe hypoglycemia occurred 10
times more often with tighter BG control, and there was no difference in either
28-day or 90-day mortality based on BG control targets. Note, though, that in
even the liberal arm, the BG target was approximately 150-200 mg/dL. Glucontrol
Study: Comparing the Effects of Two Glucose Control Regimens by Insulin in
Intensive Care Unit Patients (GLUCONTROL) was a multicenter, international study
in mixed ICU populations of BG control that, again per Dr. Pastores, was stopped
earlier this year because of safety concerns. After 1100 persons (of a planned
3500) were recruited, an interim analysis showed no difference in mortality.
Among the intervention arm (tight control), nearly 20% of those who developed BG
levels below 40 mg/dL died vs 12% of persons with BG values < 40 mg/dL in the
conventional control arm (P = .0002). A final large international trial
dealing with BG control (NICE SUGAR) is planned.
In Conclusion
As with the use of corticosteroids, the emerging clinical trial experience
makes issues less clear rather than offering resolution. The data seem to
suggest that tight BG control can be associated with clear adverse events.
Additionally, it seems that the risk for harm with tight BG control may vary
with the patient's underlying illness, risk for death, and whether he/she is a
surgical or medical patient. We also presently lack tools that provide direct
continuous BG monitoring akin to what we employ to measure oxygen saturation in
the ICU. Such technology is in development and may help promote the safety of
intensive insulin therapy. Until that time, physicians need to monitor their own
rates of adverse events with tighter BG control and develop protocols that
ensure patient safety so as not to undermine the benefits of any of these
approaches.
References
- Dellinger RP, Carlet JM, Masur H, et al; Surviving Sepsis Campaign
Management Guidelines Committee. Surviving Sepsis Campaign guidelines for
management of severe sepsis and septic shock. Crit Care Med. 2004;32:858-873. Abstract
- Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in
critically ill patients. N Engl J Med. 2004;350:1629-1638. Abstract
- Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low
doses of hydrocortisone and fludrocortisone on mortality in patients with septic
shock. JAMA. 2002;288:862-871. Abstract
- Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the
effect of steroids on survival and shock during sepsis depends on the dose. Ann
Intern Med. 2004;141:47-56. Review.
- van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in
the critically ill patients. N Engl J Med. 2001;345:1359-1367. Abstract
- Krinsley JS. Effect of an intensive glucose management protocol on the
mortality of critically ill adult patients. Mayo Clin Proc. 2004;79:992-1000. Abstract
- Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in
critically ill patients. JAMA. 2003;290:2041-2047. Abstract
- Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in
the medical ICU. N Engl J Med. 2006;354:449-461. Abstract
