critical illness thereby counteracting the protein catabo-lism that occurs during critical illness.43–45 INTENSIVE INSULIN THERAPY IN THE CRITICALLY ILL Van Den Berghe et al, in a prospe
Trang 1critical illness thereby counteracting the protein
catabo-lism that occurs during critical illness.43–45
INTENSIVE INSULIN THERAPY IN THE
CRITICALLY ILL
Van Den Berghe et al, in a prospective, randomized,
controlled study involving 1548 patients, demonstrated
that intensive insulin therapy reduced mortality and
morbidity among patients admitted to a surgical critical
care unit (the Leuven Intensive Insulin Therapy
Trial).1,46These authors compared an intensive insulin
therapy regimen aimed to maintain blood glucose
be-tween 80 and 110 mg/dL with conventional treatment in
which insulin infusion was only initiated when glucose
level was greater than 215 mg/dL and maintenance of
glucose between 180 and 200 mg/dL At 12 months the
mortality was 4.6% with the intensive insulin regimen
compared with 8.0% in the control group The benefit
was most apparent in patients with greater than 5 days of
stay in the intensive care unit Tight and early glycemic
control was associated with the more rapid improvement
of insulin resistance.46 Intensive insulin therapy was
associated with reduced bloodstream infections by
46%, acute renal failure by 41%, and critical illness
polyneuropathy by 44% Using multivariate analysis the
authors suggested that improved metabolic control, as
reflected by normoglycemia, rather than the infused
insulin dose per se, was responsible for the beneficial
effects of intensive insulin therapy However, achieving
normoglycemia and the administration of insulin are
linked, and from the available evidence it appears likely
that both factors played a key role in the improved
outcome
The outcome data from the Leuven Intensive
Insulin Therapy Trial indicates that there is a direct
relationship between the degree of glycemic control and
hospital mortality.46In the long-stay patients (> 5 days
in the ICU) the cumulative hospital mortality was 15%
in patients with a mean blood glucose less than 110 mg/
dL, 25% in those with a blood glucose between 110 and
150 mg/dL, and 40% in those with a mean blood glucose
of greater than 150 mg/dL In diabetic patients with
acute myocardial infarction, therapy to maintain blood
glucose at a level below 215 mg/dL improves
out-come.24,26,27 These data suggest that even ‘‘modest’’
glycemic control will have an impact on patient outcome
This is important because in the ‘‘real world’’ it may be
difficult (if not somewhat risky) to attempt to maintain
blood glucose in the range of 80 to 110 mg/dL This
often requires the use of a continuous insulin infusion
protocol and frequent blood glucose monitoring
How-ever, this goal may only be achievable in ICUs with a
high nursing to patient ratio and close physician
super-vision On the other hand, the Leuven study showed
that to improve morbidity by reducing the incidence
of bacteremia, acute renal failure, critical illness poly-neuropathy, and transfusion requirements, a blood glucose level of less than 110 mg/dL was required
Indeed, a blood glucose level of 110–150 mg/dL was not effective on these morbidity measures as compared with> 150 mg/dL.46
Krinsley and Grissler,47evaluated an intensive glucose management protocol in 800 heterogeneous critically ill adult patients The protocol involved in-tensive monitoring and treatment to maintain plasma glucose values lower than 140 mg/dL Continuous intravenous insulin was used if glucose values exceeded
200 mg/dL The mean glucose value decreased from 152.3 to 130.7 mg/dL (p < 001), marked by a 56.3% reduction in the percentage of glucose values of
200 mg/dL or higher, without a significant change in incidence of hypoglycemia The development of new renal insufficiency decreased by 75% (p ¼ 0.03), and the number of patients undergoing transfusion of packed red blood cells decreased by 18.7% (p ¼ 04) Hospital mortality decreased by 29.3% (p ¼ 002), and length
of stay in the ICU decreased by 10.8% (p ¼ 01) In addition, intensive insulin therapy was shown to cause a significant reduction in the incidence of total nosoco-mial infections, including intravascular device, blood-stream, intravascular device–related bloodblood-stream, and surgical site infections
Grey and Perdrizet48 randomized 61 surgical ICU patients requiring treatment of hyperglycemia (glucose values > or ¼ 140 mg/dL) to receive either standard insulin therapy (target glucose range, 180 to
220 mg/dL) or strict insulin therapy (target glucose range, 80 to 120 mg/dL) throughout their ICU stay A significant reduction (p < 001) in mean daily glucose level was achieved in the strict glycemic control group (125 36 mg/dL) in comparison with the standard glycemic control group (179 61 mg/dL) A significant reduction (p < 05) in the incidence of total nosocomial infections, including intravascular device, bloodstream, and surgical wound infections, was observed in the strict glucose control group in comparison with the standard glucose control group
It is noteworthy that in the Leuven Intensive Insulin Therapy Trial, all patients received between
200 and 300 g of intravenous glucose on the day of admission followed by parenteral or enteral (or both) nutrition started on the second ICU day However, although early enteral feeding has been reported to improve organ function and decrease the length of hospital stay,49 parenteral nutrition is associated with adverse outcomes during critical illness.50Furthermore, hypocaloric enteral nutrition administered with slowly absorbed carbohydrate induces less hyperglycemia than parenteral nutrition among critically ill.51–53
Based on the foregoing results we recommend the initiation of early enteral nutrition in all ICU patients on
Trang 2the day of ICU admission.49,50,54 Enteral nutrition
should be commenced at a rate of 33 to 66% of calculated
intake (15 to 20 kcal/kg/d) and advanced to full calorific
goal of 20 to 25 kcal/kg/d over 3 to 5 days.55 Insulin
infusion should be commenced in patients with blood
glucose above 150 mg/dL (a threshold of 110 mg/dL
may be appropriate in select ICUs) Subcutaneous
in-sulin ‘‘sliding scales’’ may control stress hyperglycemia
However, an insulin infusion is recommended if the
blood glucose remains above 150 mg/dL after 24 hours
on a sliding scale
ADRENAL INSUFFICIENCY IN THE
CRITICALLY ILL
In critically ill patients there has been a great deal of
interest regarding the assessment of adrenal function and
the indications for adrenal replacement therapy.9,11,56–58
A-1, although once considered a rare diagnosis in the
ICU, is currently being reported with increased
fre-quency in critically ill patients Although the exact
incidence of A-1 varies with the diagnostic test and
concentration of cortisol used to diagnose the disorder,
in one series 61% of critically ill septic shock patients
had A-1 when a baseline cortisol concentration of
< 25 mg/dL was used as the diagnostic threshold.56
Adrenal failure can be caused by structural damage to
the adrenal gland, pituitary gland, or hypothalamus;
however, many critically ill patients develop reversible
failure of the HPA axis.9
HYPOTHALAMO-PITUITARY AXIS AND
CORTISOL DURING STRESS
Severe illness and stress activate the HPA axis and
stimulate the release of corticotropin [also known as
adrenal corticotropic hormone (ACTH)] from the
pi-tuitary, which in turn increases the release of cortisol
from the adrenal cortex This activation is an essential
component of the general adaptation to illness and stress,
and contributes to the maintenance of cellular and organ
homeostasis
CAUSES OF ADRENAL INSUFFICIENCY IN
THE INTENSIVE CARE UNIT
Acute A-1 occurs in patients who are unable to increase
their production of cortisol during acute stress This
includes patients with hypothalamic and pituitary
dis-orders (secondary A-1) and patients with destructive
diseases of the adrenal glands (primary A-1) (Table 1)
Secondary A-1 is common in patients who have been
treated with exogenous corticosteroids Increasingly A-1
is being reported in patients with sepsis, human
immu-nodeficiency virus infection, acute and subacute liver
failure, brain-dead organ donors, and cardiac surgery
patients.56,59–62 However, the most common cause of acute A-1 is sepsis and systemic inflammatory response syndrome (SIRS)56,63,64(Table 1)
PATHOPHYSIOLOGY OF A-1 DURING CRITICAL ILLNESS
Sepsis and Systemic Inflammatory Response Syndrome–Induced Acute Reversible Adrenal Insufficiency
There is increasing evidence of HPA insufficiency in critically ill septic patients,56,65 which appears to result from circulating suppressive factors released during sys-temic inflammation.66It is important to recognize these patients because this disorder has a high mortality rate if
Table 1 Etiology of Adrenal Insufficiency during Critical Illness
COMMON Reversible dysfunction of the HPA axis
Drugs
ACTH and cortisol resistance Primary and secondary
Liver disease (hepatoadrenal syndrome)
HDL (apolipoprotein-1) deficiency
Primary Fulminant hepatic failure Primary and secondary Chronic liver failure (cirrhosis) Primary
Liver transplantation Primary
Heparin-induced thrombocytopenia
Primary and secondary Brain dead organ donors Primary and secondary RARE
Metastatic cancer Primary and secondary
Granulomatous diseases Primary and secondary ACTH, adrenal corticotropic hormone; A-1, adrenal Insufficiency; HDL, high density lipoprotein; HIV, human immunodeficiency virus; HPA, hypothalamic-pituitary-adrenal; SIRS, systemic inflammatory response syndrome.
a Primary A-1 is defined as the failure of the adrenal gland to produce cortisol 9
b
Secondary A-1 is defined as adrenal failure secondary to hypo-thalmo-pituitary-axis dysfunction.9,61
Trang 3untreated.67 In our series of 59 patients with septic
shock, 15 patients (25%) had primary A-1, 10 patients
(17%) had HPA-axis failure, and 11 patients (19%) had
ACTH resistance.56Surviving septic patients had return
of adrenal function and did not require long-term
treat-ment with corticosteroids
Adrenocorticotropin and Cortisol Resistance
Patients with systemic infections [e.g., sepsis, human
immunodeficiency virus (HIV)] may acquire A-1
asso-ciated with resistance to ACTH In two recent studies in
critically ill patients, we found that 30% of patients with
septic shock and 25% of critically ill, HIV-infected
patients acquired A-1 associated with ACTH
resist-ance.59,68 In these patients pharmacological doses of
exogenous corticotropin did not increase their serum
cortisol levels, but high doses of corticotropin were able
to increase the levels into the normal range suggesting
corticotropin resistance
Ali and colleagues reported a 40% decline in the
number of glucocorticoid receptors (GRs) in the liver of
septic rats.69The decline in hormone-binding activity
was associated with a fall in GR messenger ribonucleic
acid (mRNA) Decreased affinity of the GR from
mononuclear leukocytes of patients with sepsis has
also been reported.70 In addition, Norbiato et al
re-ported resistance to glucocorticoids in patients with
acquired immunodeficiency syndrome (AIDS).68
Cor-tisol-resistant patients had clinical evidence of A-1
associated with decreased affinity of GRs for
glucocor-ticoids and decreased GR function We as well as others
have found that cortisol clearance from the circulation
is impaired in many critically ill patients.71 This
de-creased clearance reflects dede-creased tissue uptake and
metabolism of cortisol
Liver Failure–Associated Adrenal Insufficiency
(the ‘‘Hepatoadrenal’’ Syndrome)
We have found a high incidence of adrenal failure in
critically ill patients with liver disease, an entity for
which we have coined the term hepatoadrenal syndrome.72
In our study of 245 patients with hepatoadrenal
syn-drome, high density lipoprotein (HDL) level at the time
of adrenal testing was the only variable predictive of
adrenal insufficiency (p < 0001) In
vasopressor-de-pendent patients with A-1, treatment with
hydrocorti-sone was associated with a significant reduction (p < 02)
in the dose of norepinephrine at 24 hours, whereas the
dose of norepinephrine was significantly higher (p < 04)
in those patients with adrenal failure not treated with
hydrocortisone In vasopressor-dependent patients
with-out A-1, treatment with hydrocortisone did not affect
vasopressor dose at 24 hours One hundred and
forty-one of a total 340 patients (41%) died during their
hospitalization The baseline serum cortisol was 18.8 16.2 mg/dL in the nonsurvivors compared with 13.0 11.8 mg/dL in the survivors (p < 001) Of those patients with adrenal failure who were treated with glucocorticoids, the mortality rate was 26% compared with 46% (p < 002) in those who were not treated In those patients receiving vasopressor agents at the time of adrenal testing, the baseline cortisol was 10.0 4.8 mg/
dL in those with A-1 compared with 35.6 21.2 mg/dL
in those with normal adrenal function Vasopressor-dependent patients who did not have adrenal failure had a mortality rate of 75%.72
High Density Lipoprotein Deficiency and Adrenal Insufficiency
A-1 is increasingly being reported in patients with acute and subacute liver failure.60,72–75 The finding of an association between low serum apolipoprotein A-1 (Apo-1) in patients with hepatic failure and A-1 sup-ports the notion that liver disease may lead to impaired cortisol synthesis.74–76Apo-1 is the major protein com-ponent of HDL cholesterol synthesized principally by the liver Experimental studies suggest that HDL is the preferred lipoprotein source of steroidogenic substrate in the adrenal gland.76At rest and during stress, 80% of circulating cortisol is derived from plasma cholesterol, the remaining 20% being synthesized in situ from acetate and other precursors.77
Recently, mouse scavenger receptor, class B, type
1 (SR-B1) and its human homologue (CLA-1) were identified as the high affinity HDL receptor mediating selective cholesterol uptake.78 The receptor for HDL (CLA-1) is expressed at high levels in the parenchymal cells of the liver and the steroidogenic cells of the adrenal glands, ovaries, and testes CLA-1 mRNA is highly expressed in human adrenal glands, and the accumula-tion of CLA-1 messenger RNA is upregulated by adrenocorticotropin in primary cultures of normal hu-man adrenocortical cells.77Low Apo-1/HDL levels in the critically ill may be pathogenetically linked to the high incidence of adrenal failure in this group of patients Van der Voort and colleagues79demonstrated that in critically ill patients, low HDL levels were associated with an attenuated response to Synacthen
Indeed, an inverse relationship noted between proin-flammatory mediators and HDL/Apo-1 levels is asso-ciated with poor outcome in the critically ill.80This may
be mediated by low serum cortisol level and A-1, suggesting that further studies are required to define the pathogenetic role and mechanisms of altered HDL/
Apo-1 metabolism in acute illness.74
In our series of patients with end-stage liver failure, we noted an incidence of adrenal failure in
15% of patients with fulminant liver failure, 40 to 50% in patients with end-stage liver failure, and 90%
Trang 4of patients undergoing liver transplantation.72 Because
HDL is synthesized primarily by the liver and plays a
fundamental role in transporting cholesterol to the
adrenal gland, patients with the hepatoadrenal syndrome
have low HDL levels In our study, the mean HDL level
was 8 mg/dL in patients with hepatoadrenal syndrome,
whereas it was 34 mg/dL (p ¼ 01) in patients with
normal adrenal function Furthermore, a low HDL level
at admission to the ICU was predictive of the
develop-ment of adrenal failure (adrenal exhaustion syndrome) in
patients who had preserved adrenal function at
admis-sion Based on these findings, we suggest the routine
measurement of a random cortisol and HDL level in all
patients with end-stage liver disease and in all critically
ill patients at risk of adrenal failure
Endotoxemia and Adrenal Insufficiency
Apart from low HDL levels and the reduced delivery of
substrate for cortisol synthesis, other mechanisms may
contribute to the pathophysiology of the hepatoadrenal
syndrome Patients with acute and chronic liver disease
have increased levels of circulating endotoxin
[lipopoly-saccharide (LPS)] and proinflammatory mediators such
as TNF.81It is postulated that intestinal bacterial
over-growth with increased bacterial translocation, together
with reduced Kupffer cell activity and portosystemic
shunting results in systemic endotoxemia with increased
transcription of proinflammatory mediators.82,83In
ad-dition, serum endotoxin levels increase further during
the anhepatic phase of liver transplantation and remain
high for several days following transplantation.82LPS as
well as TNF may inhibit cortisol synthesis Endotoxin
has been shown to bind with high affinity to the HDL
receptor (CLA-1) with subsequent internalization of the
receptor.84,85 LPS may therefore limit the delivery of
HDL cholesterol to the adrenal gland Furthermore,
TNF as well as interleukin-1b and interleukin-6 has
been demonstrated to decrease hepatocyte synthesis and
secretion of Apo-186(Fig 1)
DIAGNOSIS OF
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FAILURE
Because there are no clinically useful tests to assess the
cellular actions of cortisol (i.e., end-organ effects), the
diagnosis of A-1 is based on the measurement of serum
cortisol levels; this has resulted in much confusion and
misunderstanding.58,87–90 Circulating cortisol is bound
to corticosteroid-binding globulin with < 10% in the
free bioavailable form During acute illness, there is an
acute decline in the concentration of
corticosteroid-binding globulin as well as decreased corticosteroid-binding affinity
for cortisol, resulting in an increase in the free
bio-logically active fraction of the hormone.65,90In addition,
the number of intracellular GRs has been reported to be
both upregulated or downregulated (tissue resistance) during stress.91,92 These data suggest that the total circulating cortisol level may be a poor indicator of glucocorticoid activity at the nuclear level Notwith-standing these caveats and the fact that we currently
do not have a test that measures glucocorticoid activity, assessment of the HPA axis is usually made on the basis
of a random (stress) cortisol level or the corticotropin stimulation test In a highly stressed patient such as with severe sepsis and other shock states a random cortisol level assesses the integrity of the entire HPA axis.88 Dysfunction at the hypothalamic, pituitary, or adrenal level will result in low circulating cortisol levels (< 20 mg/dL) A stress cortisol level of < 20 mg/dL in
a patient with refractory hypotension should be treated with low-dose (stress dose) hydrocortisone.9 Because this cutoff is rather arbitrary, a patient with a cortisol level greater than 20mg/dL but less than 35 mg/dL, who has refractory hypotension may warrant a trial of low-dose hydrocortisone It should be emphasized that a cortisol level of> 20 mg/dl does not exclude A-1 due to tissue resistance
A random cortisol level of < 15 mg/dL in a moderately stressed (vasopressor-independent) ICU pa-tient is suggestive of HPA dysfunction.57In moderately stressed patients, ‘‘adrenal reserve’’ can be assessed by the low dose (LD; 1mg) corticotropin (Synacthen) stimula-tion test A serum cortisol level of < 20 mg/dL
30 minutes after an LD corticotropin stimulation test
is suggestive of primary A-1 It is important to empha-size that the random and stimulated cortisol levels must
be interpreted in conjunction with the severity of illness and the patient’s clinical features.89 A moderately stressed ICU patient with a random cortisol level of
< 15 mg/dL or a stimulated level of < 20 mg/dL who has
no clinical signs of A-1 (unexplained fever, confusion, hemodynamic instability, or eosinophilia) does not warrant treatment with stress doses of hydrocortisone Annane et al11showed that a high baseline cortisol
as well as inability to increase cortisol by 9 mg/dL (delta cortisol) after a high dose corticotropin (250 mg tetracosactrin) stimulation test was associated with a worse likelihood of survival Following this study the delta cortisol has become the standard diagnostic test of choice to diagnose A-1 in the ICU (see later discussion) The ‘‘delta 9’’ has become the magical number that distinguishes normal adrenal function from ‘‘relative’’ adrenal failure However, the delta cortisol is a measure
of adrenal reserve and adrenal responsiveness to cortico-tropin; it does not assess the integrity of the HPA axis and is not a measure of adrenal function In a study by Dimopoulou and coauthors who evaluated the HPA axis dysfunction in critically ill patients with traumatic brain injury,> 50% of healthy volunteers had a delta cortisol of
< 9 mg/dL.93 Similarly, in a study of patients with respiratory failure and no evidence of HPA disease,
Trang 550% had a delta cortisol of< 9 mg/dL after endotracheal
intubation with midazolam anesthesia.94We believe that
the standard corticotropin stimulation test lacks
sensitiv-ity for the diagnosis of A-1.89 As already discussed, a
threshold cortisol level of < 20 g/dL is inappropriately
low in critically ill patients ‘‘Normal’’ critically ill patients
should elevate their cortisol level 25 mg/dL
Further-more, 250 mg of corticotropin is supraphysiological
( 100-fold higher than normal maximal-stress ACTH
levels).87,95The very high levels of corticotropin obtained
with 250 mg can override adrenal resistance to ACTH
and result in a normal cortisol response Therefore the
decision to treat patients with glucocorticoids should be
based on serum cortisol levels in conjunction with the
patient’s clinical features and severity of illness In
pa-tients with subtle clinical signs or a borderline random
cortisol level, a therapeutic trial of treatment with
stress-level doses of glucocorticoids may be warranted The
potential benefit of treatment with hydrocortisone in
certain patient groups, including those with severe sepsis
(not septic shock), hemodynamic instability in nonseptic
patients, severe community acquired pneumonia; patients
treated with etomidate; and patients being weaned from
mechanical ventilation, deserve further investigation
THERAPY OF ADRENAL INSUFFICIENCY
During septic shock, treatment with stress-level doses of
hydrocortisone has been demonstrated to improve
he-modynamic status, downregulate the proinflammatory
response, and improve survival10,11,96–98 Annane and
colleagues in a landmark placebo-controlled,
random-ized, double-blind, multicenter study, enrolled 300 adult
patients with septic shock after undergoing a short
high-dose (250 mg) corticotropin test.11 Patients were
ran-domly assigned to receive either hydrocortisone (50 mg
IV q6h) and fludrocortisone (50 mg tablet once daily)
(n ¼ 151) or matching placebos (n ¼ 149) for 7 days The
mortality was 53% in the corticosteroid group and 63%
in the placebo group Vasopressor therapy was
with-drawn in 40% of patients who received placebo and in
57% in the corticosteroid group (hazard ratio, 1.91; 95%
confidence interval, 1.29 to 2.84; p ¼ 001)
Marik and Zaloga compared whether a baseline
(random) cortisol concentration< 25 mg/dL was a better
discriminator of adrenal insufficiency than the standard
(250 mg) and the low-dose (1 mg) corticotropin
stim-ulation tests in 59 patients with septic shock.56
Follow-ing baseline cortisol level, patients were given 1mg of
corticotropin (low dose), followed 60 minutes later by an
injection of 249 mg of corticotropin (high-dose test)
Cortisol concentrations were obtained 30 and 60
mi-nutes after low- and high-dose corticotropin All
pa-tients were administered hydrocortisone (100 mg q8h)
for the first 24 hours while awaiting results of cortisol
assessment Patients were considered steroid responsive
if the pressor agent could be discontinued within
24 hours of the first dose of hydrocortisone
Sixty-one percent of patients met the criteria of A-1 when a baseline cortisol concentration of< 25 mg/dL was used Ninety-five percent of steroid-responsive pa-tients had a baseline cortisol concentration< 25 mg/dL
Receiver operating characteristic curve analysis revealed that a stress cortisol concentration of 23.7mg/dL was the most accurate diagnostic threshold for determination of the hemodynamic response to glucocorticoid therapy
The sensitivity of a baseline cortisol < 25 mg/dL in predicting steroid responsiveness was 96%, compared with 54% for the low-dose test and 22% for the high dose test The specificities of the tests were 57, 97, and 100%, respectively The area under the receiver operating characteristic curve of the stress (baseline) cortisol con-centration was 0.84; a stress cortisol concon-centration of 23.7 mg/dL had the best discriminating power, with a sensitivity of 0.86, a specificity of 0.66, a likelihood ratio of 2.6, a positive predictive value of 0.62, and a negative predictive value of 0.88
However, as discussed previously, it is unclear at this time whether a threshold of 20mg/dL or 25 mg/dL should be used to determine treatment with hydro-cortisone Due to poor sensitivity of low-dose and high-dose corticotropin stimulation testing we recom-mend that these tests be avoided in severely stressed, vasopressor-dependant septic shock patients to diagnose A-1.56,89,99
From a practical point of view it is reasonable to initiate treatment with low-dose steroids in any patient presenting with septic shock and refractory hypotension pending the results of random cortisol (Fig 2).97 Glu-cocorticoids should be continued in those patients with a stress cortisol level of< 20 mg/dL and in those patients with a level> 20 mg/dL who have demonstrated a clear-cut hemodynamic response (lesser vasopressor require-ment) to glucocorticoid replacement.56,64,89We believe this to be a useful (although not the only) approach to the management of adrenal failure in the critically ill patient until more specific diagnostic tests become avail-able that can quantitate glucocorticoid activity at the cellular or nuclear level The ‘‘best’’ dosing schedule has yet to be determined; however, currently hydrocortisone
at a dose of 50 mg q6h or 100 mg q8h is recommended
Alternatively hydrocortisone can be given as a 100 mg bolus, followed by an infusion at 10 mg/h This latter regimen may result in better glycemic control Hydro-cortisone should be continued for 5 to 7 days at the above dose before tapering, assuming that there is no recur-rence of signs of sepsis or shock The hydrocortisone dose should then be reduced every 2 to 3 days by 50%, unless there is clinical deterioration, which would re-quire an increase in hydrocortisone dose Currently, there are no data available to suggest how long hydro-cortisone should be continued and when and if ACTH
Trang 6testing should be performed (to confirm recovery of
adrenal function) Furthermore, although there are few
data, routine treatment with fludrocortisone is not
rec-ommended at this time
CONCLUSION
Stress hyperglycemia and A-1 are common in critically
ill patients Multiple pathogenetic mechanisms are
re-sponsible for each of these distinct metabolic syndromes;
however, increased release of proinflammatory mediators
and counterregulatory hormones may play a pivotal role
Hyperglycemia per se is proinflammatory, whereas
in-sulin has antiinflammatory properties Similarly, A-1 is
associated with a proinflammatory state, whereas steroid
supplementation attenuates cortisol deficiency and
in-flammation If untreated, both are associated with a higher mortality Currently available evidence is robust enough to suggest that a tight glycemic control with insulin and therapy of A-1 with steroid supplementation will improve survival in critically ill patients
AUTHORS’ NOTE
The authors have no financial interest in any of the products mentioned in this article
REFERENCES
1 Van den Berghe G, Wouters P, Van Weekers F, et al Intensive insulin therapy in the critically ill patients N Engl J Med 2001;345:1359–1367
Figure 2 Recommended strategy for evaluation and treatment of adrenal insufficiency among the critically ill.
Trang 72 Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F,
Wouters PJ Insulin therapy protects the central and peripheral
nervous system of intensive care patients Neurology 2005;64:
1348–1353
3 Krinsley JS Effect of an intensive glucose management
protocol on the mortality of critically ill adult patients Mayo
Clin Proc 2004;79:992–1000
4 Bochicchio GV, Sung J, Joshi M, et al Persistent
hyper-glycemia is predictive of outcome in critically ill trauma
patients J Trauma 2005;58:921–924
5 Laird AM, Miller PR, Kilgo PD, Meredith JW, Chang MC.
Relationship of early hyperglycemia to mortality in trauma
patients J Trauma 2004;56:1058–1062
6 Finney SJ, Zekveld C, Elia A, Evans TW Glucose control and
mortality in critically ill patients JAMA 2003;290:2041–2047
7 Pittas AG, Siegel RD, Lau J Insulin therapy for critically ill
hospitalized patients: a meta-analysis of randomized
con-trolled trials Arch Intern Med 2004;164:2005–2011
8 Krinsley JS Association between hyperglycemia and increased
hospital mortality in a heterogeneous population of critically
ill patients Mayo Clin Proc 2003;78:1471–1478
9 Marik PE, Zaloga GP Adrenal insufficiency in the critically
ill: a new look at an old problem Chest 2002;122:1784–1796
10 Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D,
Kupfer Y Corticosteroids for severe sepsis and septic shock: a
systematic review and meta-analysis BMJ 2004;329:489
11 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
12 Marik PE, Raghavan M Stress-hyperglycemia, insulin and
immunomodulation in sepsis Intensive Care Med 2004;30:
748–756
13 Hart BB, Stanford GG, Ziegler MG, Lake CR, Chernow B.
Catecholamines: study of interspecies variation Crit Care
Med 1989;17:1203–1222
14 Van den BG Neuroendocrine pathobiology of chronic critical
illness Crit Care Clin 2002;18:509–528
15 Siegel JH, Cerra FB, Coleman B, et al Physiological and
metabolic correlations in human sepsis: invited commentary.
Surgery 1979;86:163–193
16 Clowes GH Jr, Martin H, Walji S, Hirsch E, Gazitua R,
Goodfellow R Blood insulin responses to blood glucose levels
in high output sepsis and septic shock Am J Surg 1978;135:
577–583
17 Mizock BA Alterations in fuel metabolism in critical illness:
hyperglycaemia Best Pract Res Clin Endocrinol Metab
2001;15:533–551
18 Dahn MS, Jacobs LA, Smith S, et al The relationship of
insulin production to glucose metabolism in severe sepsis.
Arch Surg 1985;120:166–172
19 Mehta VK, Hao W, Brooks-Worrell BM, Palmer JP
Low-dose interleukin 1 and tumor necrosis factor individually
stimulate insulin release but in combination cause
suppres-sion Eur J Endocrinol 1994;130:208–214
20 McCowen KC, Malhotra A, Bistrian BR Stress-induced
hyperglycemia Crit Care Clin 2001;17:107–124
21 Frankenfield DC, Omert LA, Badellino MM, et al
Corre-lation between measured energy expenditure and clinically
obtained variables in trauma and sepsis patients JPEN J
Parenter Enteral Nutr 1994;18:398–403
22 Norhammar AM, Ryden L, Malmberg K Admission plasma
glucose: independent risk factor for long-term prognosis after
myocardial infarction even in nondiabetic patients Diabetes Care 1999;22:1827–1831
23 Zindrou D, Taylor KM, Bagger JP Admission plasma glucose: an independent risk factor in nondiabetic women after coronary artery bypass grafting Diabetes Care 2001;24:
1634–1639
24 Malmberg K, Norhammar A, Wedel H, Ryden L Glyco-metabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study Circulation 1999;
99:2626–2632
25 Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC.
Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview Stroke 2001;32:
2426–2432
26 Malmberg K Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group BMJ 1997;314:1512–
1515
27 Malmberg K, Ryden L, Efendic S, et al Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year J Am Coll Cardiol 1995;26:57–65
28 Woo J, Lam CW, Kay R, Wong AH, Teoh R, Nicholls MG.
The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke Arch Neurol 1990;47:1174–1177
29 Garg R, Tripathy D, Dandona P Insulin resistance as a proinflammatory state: mechanisms, mediators, and thera-peutic interventions Curr Drug Targets 2003;4:487–492
30 Dandona P, Aljada A, Bandyopadhyay A The potential therapeutic role of insulin in acute myocardial infarction in patients admitted to intensive care and in those with unspecified hyperglycemia Diabetes Care 2003;26:516–519
31 Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den
BG Intensive insulin therapy exerts antiinflammatory effects
in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels J Clin Endocrinol Metab 2003;88:1082–1088
32 Ceriello A, Bortolotti N, Motz E, et al Meal-induced oxidative stress and low-density lipoprotein oxidation in dia-betes: the possible role of hyperglycemia Metabolism 1999;48:
1503–1508
33 Mowlavi A, Andrews K, Milner S, Herndon DN, Heggers JP.
The effects of hyperglycemia on skin graft survival in the burn patient Ann Plast Surg 2000;45:629–632
34 Furnary AP, Zerr KJ, Grunkemeier GL, Starr A Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures Ann Thorac Surg 1999;67:352–360
35 Zerr KJ, Furnary AP, Grunkemeier GL, Bookin S, Kanhere
V, Starr A Glucose control lowers the risk of wound infection
in diabetics after open heart operations Ann Thorac Surg 1997;63:356–361
36 McManus LM, Bloodworth RC, Prihoda TJ, Blodgett JL, Pinckard RN Agonist-dependent failure of neutrophil function in diabetes correlates with extent of hyperglycemia.
J Leukoc Biol 2001;70:395–404
Trang 837 Evans TW Hemodynamic and metabolic therapy in critically
ill patients N Engl J Med 2001;345:1417–1418
38 Vanhorebeek I, De Vos R, Mesotten D, Wouters PJ,
Wolf-Peeters C, Van den BG Protection of hepatocyte
mitochon-drial ultrastructure and function by strict blood glucose
control with insulin in critically ill patients Lancet 2005;
365:53–59
39 Dandona P, Aljada A, Mohanty P, et al Insulin inhibits
intranuclear nuclear factor kappaB and stimulates IkappaB in
mononuclear cells in obese subjects: evidence for an
anti-inflammatory effect? J Clin Endocrinol Metab 2001;86:3257–
3265
40 Langouche L, Vanhorebeek I, Vlasselaers D, et al Intensive
insulin therapy protects the endothelium of critically ill
patients J Clin Invest 2005;115:2277–2286
41 Whalen MJ, Doughty LA, Carlos TM, Wisniewski SR,
Kochanek PM, Carcillo JA Intercellular adhesion molecule-1
and vascular cell adhesion molecule-1 are increased in the
plasma of children with sepsis-induced multiple organ failure.
Crit Care Med 2000;28:2600–2607
42 Boldt J, Wollbruck M, Kuhn D, Linke LC, Hempelmann G.
Do plasma levels of circulating soluble adhesion molecules
differ between surviving and nonsurviving critically ill
patients? Chest 1995;107:787–792
43 Sakurai Y, Aarsland A, Herndon DN, et al Stimulation of
muscle protein synthesis by long-term insulin infusion in
severely burned patients Ann Surg 1995;222:283–294
44 Gore DC, Wolf SE, Sanford AP, Herndon DN, Wolfe RR.
Extremity hyperinsulinemia stimulates muscle protein
syn-thesis in severely injured patients Am J Physiol Endocrinol
Metab 2004;286:E529–E534
45 Woolfson AM, Heatley RV, Allison SP Insulin to inhibit
protein catabolism after injury N Engl J Med 1979;300:14–
17
46 Van den BG, Wouters PJ, Bouillon R, et al Outcome
benefit of intensive insulin therapy in the critically ill: insulin
dose versus glycemic control Crit Care Med 2003;31:359–
366
47 Krinsley J, Grissler B Intensive glycemic management in
critically ill patients Jt Comm J Qual Patient Saf 2005;31:
308–312
48 Grey NJ, Perdrizet GA Reduction of nosocomial infections
in the surgical intensive-care unit by strict glycemic control.
Endocr Pract 2004;10(Suppl 2):46–52
49 Marik PE, Zaloga GP Early enteral nutrition in acutely ill
patients: a systematic review Crit Care Med 2001;29:2264–
2270
50 Marik PE, Pinsky M Death by parenteral nutrition Intensive
Care Med 2003;29:867–869
51 Dickerson RN Hypocaloric feeding of obese patients in the
intensive care unit Curr Opin Clin Nutr Metab Care
2005;8:189–196
52 Moore FA, Feliciano DV, Andrassy RJ, et al Early enteral
feeding, compared with parenteral, reduces postoperative
septic complications: the results of a meta-analysis Ann Surg
1992;216:172–183
53 Jenkins DJ, Ghafari H, Wolever TM, et al Relationship
between rate of digestion of foods and post-prandial
glycaemia Diabetologia 1982;22:450–455
54 Marik PE, Zaloga GP Gastric versus post-pyloric feeding: a
systematic review Crit Care 2003;7:R46–R51
55 Krishnan JA, Parce PB, Martinez A, Diette GB, Brower RG.
Caloric intake in medical ICU patients: consistency of care
with guidelines and relationship to clinical outcomes Chest 2003;124:297–305
56 Marik PE, Zaloga GP Adrenal insufficiency during septic shock Crit Care Med 2003;31:141–145
57 Cooper MS, Stewart PM Corticosteroid insufficiency in acutely ill patients N Engl J Med 2003;348:727–734
58 Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin JAMA 2000;283:1038–1045
59 Marik PE, Kiminyo K, Zaloga GP Adrenal insufficiency in critically ill patients with human immunodeficiency virus Crit Care Med 2002;30:1267–1273
60 Harry R, Auzinger G, Wendon J The clinical importance of adrenal insufficiency in acute hepatic dysfunction Hepatology 2002;36:395–402
61 Dimopoulou I, Tsagarakis S, Anthi A, et al High prevalence
of decreased cortisol reserve in brain-dead potential organ donors Crit Care Med 2003;31:1113–1117
62 Kilger E, Weis F, Briegel J, et al Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery Crit Care Med 2003;31:1068–1074
63 Marik PE, Zaloga GP The central nervous system hypo-thalamic-pituitary-adrenal axis in sepsis Crit Care Med 2002; 30:490–491
64 Raghavan M, Marik PE Management of sepsis during the early ‘‘golden hours.’’ J Emerg Med 2006; In press
65 Beishuizen A, Thijs LG, Vermes I Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma Intensive Care Med 2001;27:1584– 1591
66 Zaloga GP Sepsis-induced adrenal deficiency syndrome Crit Care Med 2001;29:688–690
67 Schroeder S, Wichers M, Klingmuller D, et al The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone Crit Care Med 2001;29:310–316
68 Norbiato G, Bevilacqua M, Vago T, et al Cortisol resistance
in acquired immunodeficiency syndrome J Clin Endocrinol Metab 1992;74:608–613
69 Ali M, Allen HR, Vedeckis WV, Lang CH Depletion of rat liver glucocorticoid receptor hormone-binding and its mRNA
in sepsis Life Sci 1991;48:603–611
70 Molijn GJ, Koper JW, van Uffelen CJ, et al Temperature-induced down-regulation of the glucocorticoid receptor in peripheral blood mononuclear leucocyte in patients with sepsis or septic shock Clin Endocrinol (Oxf) 1995;43:197– 203
71 Melby JC, Spink WW Comparative studies on adrenal cortical function and cortisol metabolism in healthy adults and
in patients with shock due to infection J Clin Invest 1958; 37:1791–1798
72 Marik PE, Gayowski T, Starzl TE The hepatoadrenal syndrome: a common yet unrecognized clinical condition Crit Care Med 2005;33:1254–1259
73 Singh N, Gayowski T, Marino IR, Schlichtig R Acute adrenal insufficiency in critically ill liver transplant recipients Implications for diagnosis Transplantation 1995;59:1744– 1745
74 Marik PE Adrenal insufficiency: the link between low apolipoprotein A-1 levels and poor outcome in the critically ill? Crit Care Med 2004;32:1977–1978
Trang 975 Yaguchi H, Tsutsumi K, Shimono K, Omura M, Sasano H,
Nishikawa T Involvement of high density lipoprotein as
substrate cholesterol for steroidogenesis by bovine adrenal
fasciculo-reticularis cells Life Sci 1998;62:1387–1395
76 Borkowski AJ, Levin S, Delcroix C, Mahler A, Verhas V.
Blood cholesterol and hydrocortisone production in man:
quantitative aspects of the utilization of circulating cholesterol
by the adrenals at rest and under adrenocorticotropin
stimulation J Clin Invest 1967;46:797–811
77 Liu J, Heikkila P, Meng QH, Kahri AI, Tikkanen MJ,
Voutilainen R Expression of low and high density lipoprotein
receptor genes in human adrenals Eur J Endocrinol 2000;
142:677–682
78 Calvo D, Gomez-Coronado D, Lasuncion MA, Vega MA.
CLA-1 is an 85-kD plasma membrane glycoprotein that acts
as a high-affinity receptor for both native (HDL, LDL, and
VLDL) and modified (OxLDL and AcLDL) lipoproteins.
Arterioscler Thromb Vasc Biol 1997;17:2341–2349
79 van der Voort PH, Gerritsen RT, Bakker AJ, Boerma EC,
Kuiper MA, de Heide L HDL-cholesterol level and cortisol
response to synacthen in critically ill patients Intensive Care
Med 2003;29:2199–2203
80 Chenaud C, Merlani PG, Roux-Lombard P, et al Low
apolipoprotein A-1 level at intensive care unit admission and
systemic inflammatory response syndrome exacerbation Crit
Care Med 2004;32:632–637
81 Mookerjee RP, Sen S, Davies NA, Hodges SJ, Williams R,
Jalan R Tumour necrosis factor alpha is an important
mediator of portal and systemic haemodynamic derangements
in alcoholic hepatitis Gut 2003;52:1182–1187
82 Yokoyama I, Gavaler JS, Todo S, Miyata T, Van Thiel
DH, Starzl TE Endotoxemia is associated with renal
dysfunction in liver transplantation recipients during the
first postoperative week Hepatogastroenterology 1995;42:
205–208
83 Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin-Dusting
J The effect of selective intestinal decontamination on the
hyperdynamic circulatory state in cirrhosis: a randomized trial.
Ann Intern Med 2003;139:186–193
84 Vishnyakova TG, Bocharov AV, Baranova IN, et al Binding
and internalization of lipopolysaccharide by CLA-1, a human
orthologue of rodent scavenger receptor B1 J Biol Chem
2003;278:22771–22780
85 Baranova I, Vishnyakova T, Bocharov A, et al
Lipopoly-saccharide down regulates both scavenger receptor B1 and
ATP binding cassette transporter A1 in RAW cells Infect
Immun 2002;70:2995–3003
86 Ettinger WH, Varma VK, Sorci-Thomas M, et al Cytokines decrease apolipoprotein accumulation in medium from Hep G2 cells Arterioscler Thromb 1994;14:8–13
87 Soni A, Pepper GM, Wyrwinski PM, et al Adrenal insufficiency occurring during septic shock: incidence, out-come, and relationship to peripheral cytokine levels Am J Med 1995;98:266–271
88 Marik P, Zaloga G Prognostic value of cortisol response in septic shock JAMA 2000;284:308–309
89 Marik PE Unraveling the mystery of adrenal failure in the critically ill Crit Care Med 2004;32:596–597
90 Hamrahian AH, Oseni TS, Arafah BM Measurements of serum free cortisol in critically ill patients N Engl J Med 2004;350:1629–1638
91 Sun X, Fischer DR, Pritts TA, Wray CJ, Hasselgren PO.
Expression and binding activity of the glucocorticoid receptor are upregulated in septic muscle Am J Physiol Regul Integr Comp Physiol 2002;282:R509–R518
92 Liu DH, Su YP, Zhang W, et al Changes in glucocorticoid and mineralocorticoid receptors of liver and kidney cytosols after pathologic stress and its regulation in rats Crit Care Med 2002;30:623–627
93 Dimopoulou I, Tsagarakis S, Kouyialis AT, et al Hypothala-mic-pituitary-adrenal axis dysfunction in critically ill patients with traumatic brain injury: incidence, pathophysiology, and relationship to vasopressor dependence and peripheral inter-leukin-6 levels Crit Care Med 2004;32:404–408
94 Schenarts CL, Burton JH, Riker RR Adrenocortical dysfunction following etomidate induction in emergency department patients Acad Emerg Med 2001;8:1–7
95 Drucker D, Shandling M Variable adrenocortical function in acute medical illness Crit Care Med 1985;13:477–479
96 Keh D, Boehnke T, Weber-Cartens S, et al Immunologic and hemodynamic effects of ‘‘low-dose’’ hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, cross-over study Am J Respir Crit Care Med 2003;167:512–520
97 Dellinger RP, Carlet JM, Masur H, et al Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock Crit Care Med 2004;32:858–873
98 Briegel J, Forst H, Haller M, et al Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospec-tive, randomized, double-blind, single-center study Crit Care Med 1999;27:723–732
99 Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers
W Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease J Clin Endocrinol Metab 1998;83:1558–1562
Trang 10Hematologic Disorders in Critically Ill
Patients
ABSTRACT
Hematologic disorders are frequently encountered in the intensive care unit Thrombocytopenia, often defined as a platelet count below 100,000/mL, is common in critically ill patients and may be associated with adverse outcomes A systematic evaluation
of clinical and laboratory findings is necessary to ascertain the cause of the thrombocyto-penia and to determine the correct therapy Recognition of heparin-induced thrombocy-topenia (HIT) is particularly important, given the risk of thrombosis associated with this condition Prompt cessation of all heparin products is required, and anticoagulation with a direct thrombin inhibitor is recommended if HIT is strongly suspected Coagulopathies are also common in the critically ill, and are often due to vitamin K deficiency or disseminated intravascular coagulation (DIC) A careful history and interpretation of clotting studies are useful in defining the coagulation defect Advances in understanding the pathogenesis of DIC have generated new treatment approaches, such as the use of recombinant activated protein C Recombinant factor VIIa (rFVIIa) is a novel drug approved for use in patients with congenital hemophilias and inhibitors Although its use as a hemostatic agent is currently being evaluated in several off-label scenarios, including trauma, intracerebral hemorrhage, and liver disease, there are limited data to guide therapy in these conditions
KEYWORDS:Thrombocytopenia, coagulopathy, heparin-induced thrombocytopenia, disseminated intravascular coagulation, recombinant factor VIIa
Hematologic disorders are common among
crit-ically ill patients and frequently contribute to adverse
outcomes This review describes the most frequent
non-neoplastic hematologic problems encountered in the
intensive care unit and summarizes current approaches
to diagnosis and management
THROMBOCYTOPENIA IN THE INTENSIVE
CARE UNIT
Thrombocytopenia is one of the most common
labo-ratory abnormalities in the intensive care unit (ICU) It
may occur via several mechanisms and in a variety of
clinical scenarios Thrombocytopenia may result in a bleeding diathesis necessitating transfusions; it may also predict for increased morbidity and mortality Successful management of thrombocytopenia requires prompt and accurate recognition of its underlying cause Drug-induced thrombocytopenia can be partic-ularly challenging because many critically ill patients receive multiple medications Heparin-induced throm-bocytopenia is of special concern, given the associated risk of thrombosis and the unique treatment of this disorder
Thrombocytopenia is frequently defined as a platelet count below 100,000/mL The incidence of
1
Division of Hematology/Oncology, University of Virginia School of
Medicine, Charlottesville, Virginia.
Address for correspondence and reprint requests: Michael E.
Williams, M.D., Hematology/Oncology Division, Box 800716,
Uni-versity of Virginia School of Medicine, Jefferson Park Ave.,
Charlot-tesville, VA 22908 E-mail: mew4p@virginia.edu.
Non-pulmonary Critical Care: Managing Multisystem Critical Illness; Guest Editor, Curtis N Sessler, M.D.
Semin Respir Crit Care Med 2006;27:286–296 Copyright # 2006
by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,
NY 10001, USA Tel: +1(212) 584-4662.
DOI 10.1055/s-2006-945529 ISSN 1069-3424.
286