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29 Glycemic Control and Insulin Resistance
Fig. 29.2 Graphic representation
of glucose variability. Both graphs represent patients with the same mean serum glucose values ( thick horizontal line ), but graph A represents higher variability with hypoglycemic episodes, despite a normal mean glucose ( a ) high variability ( b ) low variability (Modifi ed with permission from the American College of Chest Physicians. Egi
4 ] )
et al. [
ab
180
145
mg/dl
347
mg/dl
180
145
110
70
35
0
0
6
110
70
35
0
0
(hours) (hours)
Table 29.2 Current specialty society recommendations for blood glucose targets in ICU patients
Organization Recommendation Society of Critical Care Medicine [ Surviving Sepsis Campaign 2012 [ American Association of Clinical Endocrinologists and American Diabetes Association Consensus
Statement [ American College of Physicians [
71 ]
50 ] <150 mg/dl, absolutely <180 mg/dl
70 ] <180 mg/dl
140–180 mg/dl
72 ] 140–200 mg/dl
6
comes than those who were artifi cially normalized. A recent Australian observational study [ 48 ] found that septic patients who developed mild hyperglycemia (155 mg/dl) actually had better outcomes than those who remained normoglycemic, suggesting that there may be some benefi t to mild hypergly­cemia. Acute mild hyperglycemia may indeed be an adaptive survival response [ 49 ] and only harmful when excessive or prolonged, much like tachycardia.
Multiple guidelines from specialist societies no longer advocate strict glycemic control. Most recommend a target range of 140–180 mg/dl (Table 29.2 ). The paradigm of glu- cose control has not quite turned full circle to allowing fl orid hyperglycemia, but certainly artifi cial strict “normalization” is no longer suggested practice.

Glucose Measurement in the ICU

An obvious problem with hyper- or (hypo)glycemia is that accurate treatment is impossible without precise measure­ment. Point of care (POC) glucometers are widely used for rapid bedside glucose determinations in ICU patients, but persistent concerns remain about their accuracy in critically ill patients [ 50 ]. They were designed to be used in an outpa- tient setting in noncritically ill patients. Samples analyzed by POC meters can be affected by anemia, elevated pO 2 , or edema fl uid [ 51 ]. Regulatory standards allow POC glucom- eters up to a 20 % error [ within the range of the relatively mild (75 mg/dl) hypoglyce­mia that has been associated with adverse outcomes and
50 ]; but in ICU patients, this is well
348
R.N. Lesperance and O.D. Guillamondegui
death. Several studies of POC glucometers used for bedside measurement and titration of insulin infusions have found that while most measurements will adequately correlate, a signifi cant number will deviate from values obtained by cen­tral laboratory analysis [
52 ]. Variability among values
obtained from arterial and capillary samples, and those obtained from central lab-measured samples, is frequently large enough to change insulin infusion rates [ 53 ].
The source of the samples is just as important. Samples drawn from central venous catheters can be contaminated with glucose-containing infusions, or diluted by infusions without, even if infusions are temporarily paused or running in adjacent lumens of multi-lumen catheters. Laboratory managers have identifi ed wide variances in repeat samples sent within 15 min from the same patient, suggesting a rec­ognized error in sample handling by bedside personnel [ 54 ]. Capillary (fi nger stick) samples should be avoided if at all possible, since they have regularly been found to not corre­late well with central samples in critically ill patients demon­strating shock or systemic edema [ 55 , 56 ].

Recent Technological Developments

in prospective studies to increase compliance with strict glu­cose control targets while decreasing rates of hypoglycemia and glucose variability [
63 , 64 ].
There are multiple algorithms available which, when compared against hypothetical patients, vary widely in their prescribed insulin doses [
65 , 66 ]. Different algorithms may
be appropriate for different categories of patients or clinical settings [
60 ]. This may be the reason a recent large multi-
center RCT using CDSS to achieve tight glucose control was (once again) unable to fi nd a benefi t [ 67 ].
Bringing together both CGM and CDSS is the concept of a “closed-loop” glycemic control system, also referred to as an “artifi cial pancreas.” The processes of glucose monitor­ing, calculation of insulin infusion and administration, are automated without human input. Such “artifi cial pancreas” systems have been used in Japan for over 20 years for peri­operative glucose control [
68 ] but have not yet found wide-
spread acceptance in ICUs elsewhere nor have they been tested against other systems in large-scale studies for safety, effi cacy, or cost-effectiveness. Nonetheless, they offer the tantalizing prospect of delivering the benefi ts of strict glu­cose control without hypoglycemia while simultaneously reducing nursing workloads [
57 , 69 ].
If episodic hypoglycemia or excessive glucose variability contributed to the increased mortality seen in studies such as NICE-SUGAR, then more accurate methods of measuring glucose and delivering insulin (or avoiding hypoglycemia) might conceivably deliver the promised benefi ts of tighter glucose control.
Signifi cant physiologic response to insulin can occur in 10–15 min, but in most insulin infusion protocols, serum glucose is checked hourly. Measuring glucose more fre­quently might improve the accuracy of insulin infusions and possibly detect otherwise missed hypoglycemic episodes but would impose a heavy workload burden on busy bedside nurses. Continuous glucose monitoring (CGM) refers to a set of technologies that may allow more frequent or even real- time measurement of glucose [ 57 , 58 ]. These technolo- gies range from microdialysis membranes implanted in cen­tral venous catheters to devices implanted in the subcutaneous tissue utilizing RFID tags for wireless com­munication [ 59 , 60 ]. Visual or audible alarms could alert bedside personnel to glucose readings outside of pre-set parameters. The expense of testing and adopting new sys­tems may be offset to some extent by decreasing nursing workload in the ICU [ 61 ].
Computerized decision support systems (CDSSs) are computer-based advisers for dosing insulin infusions and have the potential to decrease variability in insulin dosing. Computerized protocols may allow “tighter” control of blood sugar with a lower incidence of hypoglycemic events, as compared to written protocols [
62 ]. CDSS have been shown
Conclusion
Hyperglycemia is common in ICU patients with or with­out a history of diabetes and until 2001 not aggressively treated in most ICUs. Despite the widespread adoption of strict glucose control protocols due to the Leuven studies, subsequent studies failed to replicate their improved out­comes. Concerns persist that higher rates of hypoglyce­mia with strict glucose control may be the reason for lack of benefi t and the higher mortality seen in the NICE­SUGAR trial. Most recommendations from critical care and endocrine specialty societies suggest glucose targets for ICU patients in the range of 140–180 mg/dl [ 50 , 70 – 72 ], although the results of one meta- analysis suggest there may be a benefi t to stricter control in surgical ICU patients [ 21 ]. Validated protocols should be used to dose continuous insulin infusions used in ICUs, and POC glu­cometers should be used cautiously in critically ill patients. The development of continuous glucose moni­toring and closed-loop insulin delivery systems may reduce ICU nurse workload and reduce hypoglycemic events while still delivering tight glucose control.

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Critical Illness-Related Corticosteroid Insufficiency in the Intensive Care Patient

Noelle N. Saillant and Carrie Sims
3 0

Introduction

The ability of the human body to mount a hormonal response to severe physiologic stress is a critical adaptation needed to maintain homeostasis in the face of life-threatening illness. The so-called “fi ght or fl ight” response is primarily achieved via the hypothalamic-pituitary (HPA) axis and results in increased cortisol production. Cortisol enables alternative energy resources to be utilized rapidly, dampens the infl am­matory response, and sustains hemodynamic stability through fl uid retention and enhanced catecholamine sensitiv­ity [
1 ]. Although essential for survival in the acute phase, the
HPA axis may become dysfunctional and maladaptive dur­ing prolonged phases of critical illness. Historically, the terms “absolute adrenal insuffi ciency” or “relative adrenal insuffi ciency” were used to describe the phenomenon of HPA axis dysfunction during critical illness. The use of these labels, however, has been discouraged by consensus opinion [ 2 ] in favor of the term critical illness-related corticosteroid insuffi ciency (CIRCI).
CIRCI is defi ned as a complex, proinfl ammatory state manifesting as “inadequate cellular corticosteroid activity” for the demand of the physiologic stress suffered by the patient [ low ACTH value [ resistance to corticosteroids at the tissue level [ 4 – 6 ]. Dysfunction may occur at any point in the HPA axis and results in inadequate cortisol production and/or diminished sensitivity to the corticosteroid hormones.
2 ]. The typical constellation of features includes a
3 ], an elevated plasma cortisol level, and

Physiology of the HPA Axis

Corticosteroid secretion begins with the paraventricular nuclei (PVN) of the hypothalamus. Stimulated by the circa­dian cycle of the superchiasmatic nucleus (SCN), or by a stress signal, the PVN releases corticotropin-releasing hor­mone (CRH) and arginine vasopressin. CRH stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH) that in turn stimulates the adrenal gland to secrete cortisol. Secreted cortisol can either bind to circulating pro­teins and thus remain inactive or may exist as a “free” hor­mone capable of binding to intracellular tissue glucocorticoid (GR) and mineralocorticoid receptors (MR). In the healthy state, the release of glucocorticoid has a circadian pattern based on ACTH secretion, with an early morning peak super­imposed on basal secretion with smaller fl uctuations through­out the day.
In response to acute stress, the HPA axis can be modu­lated to increase or decrease glucocorticoid production. For example, catecholamines enhance the HPA response to stress by stimulating CRH secretion. In turn, the release of CRH augments the release of norepinephrine. Free cortisol, on the other hand, downregulates the HPA axis and serves as a neg­ative feedback to modulate its own release [ 1 ]. This tightly controlled system sensitively responds to external and inter­nal stimuli (see Fig.
30.1 ).

The Systemic Effects of Cortisol

Cortisol is a glucocorticoid hormone that directly infl uences
N. N. Saillant , MD (*) Department of Surgery, Beth Israel Deaconess Medical Center , Boston , MA 02115 , USA
nsaillan@bidmc.harvard.edu
e-mail: C. Sims , MD, MS
Division of Trauma, Surgical Critical Care, and Emergency Surgery, Department of Surgery , University of Pennsylvania , Philadelphia , PA 19104 , USA
carrie.sims@uphs.upenn.edu
e-mail:
© Springer International Publishing Switzerland 2016 N.D. Martin, L.J. Kaplan (eds.), Principles of Adult Surgical Critical Care, DOI 10.1007/978-3-319-33341-0_30
endocrine, metabolic, and immunologic functions. As part of the “fi ght of fl ight” response, cortisol enhances the availability of energetic substrates by antagonizing the effects of insulin. Decreased insulin sensitivity not only directly affects glucose utilization at the tissue level, but also promotes hyperglycemia by enhancing gluconeogenesis and glycogenolysis. Cortisol also modulates the immune response to physiologic stress. Glucocorticoid secretion dampens cell- mediated immunity, as
351
352
N.N. Saillant and C. Sims
Stress
Catecholamines
ACTH Independent Pathways
IL-1, IL-6, TNF-a, Vasopressin, Endothelin, ANF, MIF, TLR
Fig. 30.1 The hypothalamic-pituitary axis (HPA axis). Stress signals
the paraventricular nucleus (PVN) of the hypothalamus to produce and release the corticotropin-releasing hormone (CRH). CRH stimulates the anterior pituitary to release the adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal glands to produce and release the stress hormone cortisol. Cortisol then provides negative feedback to diminish the release of CRH and ACTH. Catecholamines are an alternative stimulus for CRH production. IL-1, IL-6, TNF-α, vasopressin, endothelin, ANF, MIF, and TLR may trigger ACTH release that is independent of hypothalamic control
well as decreases cytokine and histamine responsiveness. This immunologic downregulation prevents the proinfl ammatory reaction to sepsis or injury from becoming over exuberant. However, states of prolonged glucocorticoid excess may lead to profound immunosuppression. Lastly, cortisol is essential for maintaining vascular tone and stability. As an important regulator of ion homeostasis, cortisol is necessary for sodium retention and potassium wasting. Cortisol also enhances vas­cular smooth muscle tone and reduces nitric oxide-mediated vasodilation. Without cortisol, patients experience severe sodium wasting, hypovolemia, and decreased vascular tone that rapidly leads to cardiovascular disease and death [ 7 ].
(+)
Anterior pituitary
CRH
-
ACTH
Adrenal gland
PVN
Cortisol
+)
(
(
)
-

Cortisol Synthesis

The production of cortisol primarily occurs in the adrenal zona fasciculata via the steroidogenic conversion of choles­terol to pregnenolone to cortisol [ not store cortisol, any augmentation in cortisol level must be coupled with increased steroidogenesis and de novo synthesis. Thus glucocorticoid levels follow real-time bodily demand.
5 ]. Because the body does

Critical Illness

Severe stress triggers the PVN to augment ACTH secretion leading to the increased production and release of cortisol [ However, in prolonged critical illness, there appears to be a paradoxic “ACTH-cortisol dissociation.” Specifi cally, overall
)
(
-
free plasma cortisol levels tend to be several-fold higher in critically ill patients, while ACTH values are notably lower in healthy patients. Theoretically, elevated free cortisol levels could be attributed to three possible mechanisms: increased production, increased liberation of free hormone, or dimin­ished breakdown.
Increased cortisol production through the traditionally described pathway is unlikely to account for the elevated cor­tisol levels observed. Given that this is not from ACTH stimu­lation, the increased cortisol levels observed are the result of activating ACTH-independent pathways. It has been postu­lated that cytokines (IL-1, Il-6, TNF α), arginine vasopressin, endothelin, and atrial natriuretic factor may be responsible for activating this alternative pathway activation during severe stress [
8 , 9 ]. A second interesting association has linked mac-
rophage migration inhibitory factor (MIF) and Toll-like recep­tors (TLR) to this dysfunction of the HPA axis. This observation may account for the higher occurrence of CIRCI during sepsis over other forms of critical illness (see Fig. 30.1 ).
Increased liberation of free hormone is also responsible for the observed effects of illness on glucocorticoid pathways. The cortisol’s effect on tissue function is dependent on its “physiologic availability,” a property contingent on circulat­ing protein levels. Over 90 % of secreted cortisol is physio­logically “inactive” because it is bound to corticosteroid-binding globulin (CBG) and albumin. CBG is best described as a high-affi nity low-capacity binding protein. As CBG saturates, the role of albumin as a carrier becomes increasingly impor­tant. During states of illness, there may be a 50 % reduction in both CBG and albumin leading to altered free hormone con­centrations, with clinical signifi cance noted when albumin levels are less than 2.5 g/dL [
The most signifi cant mechanism for the elevated gluco­corticoid levels in critical illness, however, appears to be diminished cortisol breakdown. In a study of 158 ICU patients versus age-matched controls, Boonen et al. demon­strated that the half-life of cortisol was fi ve times longer in the setting of critical illness. This decreased cortisol clear­ance appears to be the result of impaired cortisol reductase activity in the liver and adipose tissue and diminished expression of cortisol-metabolizing hormones [ has been hypothesized that the reduced clearance of stress hormone in times of illness may be energetically benefi cial; that is, high cortisol levels are maintained while the energetic expenditure required to synthesize new hormone is mini­mized. This mechanism would also lead to increased negative feedback on the HPA axis and explain the decreased levels of ACTH in ICU patients.
10 ].
1 ].
11 , 12 ]. It
30 Critical Illness-Related Corticosteroid Insuffi ciency in the Intensive Care Patient
353
Table 30.1 Medications that may affect the HPA axis [ 5 , 9 ]
Effect on HPA axis Medications Binding proteins Estrogen, OCPs Interfere with glucocorticoid
synthesis Direct antiglucocorticoid
activity Mimic or cause glucocorticoid
feedback and suppress HPA Increase cortisol metabolism Rifampin, phenytoin Downregulate receptor Antidepressants (clomipramine,
Etomidate, ketoconazole, aminoglutethimide, metyrapone
RU486
Exogenous glucocorticoids, medroxyprogesterone, megestrol
amitriptyline, sertraline, paroxetine, and venlafaxine)
It is important, however, to realize that the increased level of plasma cortisol may not necessarily translate into enhanced target organ effects. Circulating levels of cortisol do not nec­essarily correlate with tissue concentrations. Furthermore, the regulation of tissue response can be modulated at the glu­cocorticoid receptor (GR) and mineralocorticoid receptor (MR) level [ 5 , 13 ]. Animal and human models have shown evidence that the GR receptor is downregulated in protracted illness. Perhaps the best evidence is from ARDS patients showing markedly reduced nuclear density of the GR com­plex. This reduction in nuclear GR was observed in the set­ting of normal serum cortisol levels, thus supporting the concept that end-organ response to cortisol may be impaired despite adequate serum levels [ 13 ].
Aside from HPA dysfunction, a number of other factors may also contribute to insuffi cient adrenal function in states of severe illness. There is evidence that during prolonged ill­ness the health of the adrenal gland is ultimately compro­mised in the ACTH depleted state. Autopsy fi ndings of the adrenal gland of patients in the ICU for >7 days showed evi­dence of cholesterol depletion and loss architecture of the gland without the trophic stimulation of ACTH. This obser­vation may have signifi cant clinical implications during the protracted phases of critical illness [
12 ].
Hemorrhage, trauma, primary or metastatic cancers, and infections can lead to adrenal insuffi ciency in the ICU patient through destruction of the adrenal or pituitary glands. Certain drugs commonly used in the ICU setting may also contribute to primary or secondary adrenal dysfunction; however this is beyond the scope of this chapter (see Table
30.1 ).

Diagnosing CIRCI

The underlying pathophysiology of CIRCI is a proinfl amma­tory state. However the exact diagnostic criteria have yet to be defi ned. The best clinical indicator of potential CIRCI is the presence of severe hypotension refractory to vasopressor support and volume resuscitation. Patients with CIRCI are frequently hyperdynamic, with variable systemic vascular
resistance depending on the underlying pathology (sepsis, cardiogenic shock).
Hypoglycemia and eosinophilia, however, are relatively common features; however hyponatremia and hyperkalemia are less prominent in CIRCI than in Addison’s disease.
The use of serum cortisol levels and provocative testing to diagnose CIRCI is no longer recommended and repre­sents a departure from the previous diagnostic recommen­dations [ 5 , 14 , 15 ].
Historically, three tests were used to diagnose adrenal dysfunction:
1. Random cortisol levels
2. ACTH provocative testing:
(a) High-dose cosyntropin stimulation test
(b) Low-dose cosyntropin stimulation test

Cortisol Levels

The use of random cortisol levels of <10 mg /dL had previ­ously been granted a 2B recommendation [ 5 ]; however this is no longer advised by expert consensus [ 14 , 15 ]. The retraction of the laboratory diagnostic criteria is due to sev­eral confounding factors in measuring cortisol for the diag­nosis of CIRCI. For one, the total serum hormone is measured by the most available assays. Given that critical illness greatly alters the amount of free hormone due to reduced protein- binding capacity, the total hormone is a less useful measure of the adequacy of the patient’s stress function. To minimize this limitation, some authors have suggested free cortisol levels and salivary cortisol levels be measured, thus representing a more accurate assessment of hormone levels in hypoproteinemic patients. To date there is insuffi cient evidence to fully support the use of free or salivary cortisol levels due to the lack of widespread avail­ability and reproducibility of the tests [ important to account for the signifi cant variation in the pro­duction of cortisol throughout an individual’s circadian cycle. The timing of total, free, or salivary cortisol samples may lead to signifi cantly different results in the same patient.
Secondly, the presence of antibodies and cortisol by­products may interfere with the reliability of commercial cortisol levels [
15 ]. An additional drawback to measuring
cortisol levels is that the reproducibility of cortisol assays is unpredictable. The CORTICUS trial highlighted signifi cant inter-assay variability with 27 % of patient samples changing class from hypofunctional to normal adrenal function depending on the location of where the specimen was tested [ 18 , 19 ]. Lastly, it should be appreciated that the total serum cortisol level is not refl ective of the tissue resistance to cortisol.
16 , 17 ]. It is also
354
N.N. Saillant and C. Sims

ACTH Stimulation Tests

ACTH provocative testing was also historically used to diag­nose CIRCI.
High-dose ACTH testing was performed by administering cosyntropin (ACTH, 250 ug) and measuring the cortisol level 30–60 min later. A delta cortisol <9 after was considered diag­nostic of relative adrenal insuffi ciency [ 20 ]. This method fell out of favor due to the concern that the supraphysiologic dose of 250 ug of cosyntropin could potentially mask ACTH resistance and thus an “appropriate” increase may not reliably refl ect a clinical insuffi ciency. As such, a lower dose of cosyntropin (1ug) was suggested. This low stimulation test appeared to be more sensitive in identifying patients with suspected adrenal insuffi ciency [ 21 , 22 ]. However, both provocative tests still fell prey to drawbacks of measuring cortisol levels detailed above.
Thus the adequacy of the patient’s stress response cannot be accurately characterized with currently available diagnos­tics. Evidence to support the fact that laboratory testing is not predictive of treatment response is garnered from random­ized trials showing response to steroid therapy is often inde­pendent of diagnostic testing [ 23 , 24 ]. The differences in total and free cortisol levels and the confounders posed by hypoproteinemia and potential tissue resistance in combina­tion with the poor reproducibility of cortisol levels make an absolute laboratory diagnosis nearly impossible. As such, clinical assessment of shock that is refractory to fl uid and vasopressor support is the primary indication for therapy ini­tiation (recommendation strength 2B [ 5 , 14 , 25 , 26 ].

Evidence for Treatment

A number of studies have evaluated the role of steroid replace­ment in septic shock with varying results. Unfortunately, many of the inconsistencies in outcomes may be in part due to notable variations in study design with regard to:
1. The type of glucocorticoid administered and the use of
additional mineralocorticoid replacement
2. The dosing of supplemental glucocorticoids – physio-
logic versus pharmacologic
3. The timing of enrollment, steroid initiation, and duration
of treatment
4. Outcomes of interest – mortality, infection, and resolution
of shock
5. Patient population treated – surgical versus medical, sep-
sis versus ARDS
Two landmark papers are critical to the discussion of treating CIRCI.
The fi rst landmark paper from Annane et al. was a French randomized controlled trial demonstrating a 20 % mortality
reduction in patients diagnosed with adrenal insuffi ciency compared to controls [ 20 ]. Patients with refractory septic shock of greater than an hour’s duration were randomized to receive either placebo or a combination of glucocorticoid (hydrocortisone 50 mg q6hr) and mineralocorticoid replace­ment (fl udrocortisone 50ug daily) for 7 days. Non-responders (defi ned as a delta cortisol of <9), who received supplemen­tal steroids, showed a 20 % reduction in mortality when com­pared to those who received placebo [ 20 ]. This landmark greatly infl uenced clinical practice in favor of steroid therapy until the CORTICUS trial challenged its fi ndings.
The CORTICUS trial represents the second notable study that questioned the use of glucocorticoids in sepsis [ 18 ]. This randomized, placebo-controlled multicenter European study failed to show a mortality benefi t between treatment and con­trol groups. A total of 499 patients underwent a cosyntropin stimulation test (250 mcg) and were randomized within 48 h to receive hydrocortisone (without additional mineralocorti­coid) or placebo for 12 days [ 18 ]. In contrast to Annane’s trial, the CORTICUS study found no statistically signifi cant differ­ence in 28-day all-cause mortality regardless of the patient’s ACTH stimulation response (35 % versus 32 % mortality). Patients who received steroids, however, did display earlier resolution of shock and decreased need for vasopressors.
In evaluating the two trials, there are some important dif­ferences that deserve mention and may account for the dif­ferences in outcomes. First, the patient populations treated by the trials were heterogeneous. CORTICUS enrolled more surgical patients (65 %) as compared to the Annane study (40 %), and the enrollment period was more generous in the CORTICUS trial (72 h versus 8 h). Secondly, the treatment groups were managed with different steroid regimens and for different lengths of time. In the French study, fl udrocortisone was given in addition to hydrocortisone for improved miner­alocorticoid coverage versus hydrocortisone alone in CORTICUS. The addition of mineralocorticoid supplemen­tation is unlikely to have contributed to the difference in mortality [
18 , 20 ]. This conclusion is drawn from the fi nd-
ings of the COIITSS trial (2010). This study specifi cally evaluated the impact of hydrocortisone alone versus hydro­cortisone plus fl udrocortisone in severe sepsis and found no added benefi t [
27 ].
Finally, the patient population was not quite as ill as the French study. This may be an important factor in explaining the different study conclusions as other trials have shown trends toward improved mortality in the severely ill. Specifi cally, these trends have been observed in patients with refractory shock. The Annane study focused on this patient group, whereas the CORTICUS trial enrolled patients regard­less of fl uid and vasopressor response. The difference in the severity of illness in the study populations is evident in higher SAPSII scores and higher mortality in the Annane study (61 % versus 32 %).
30 Critical Illness-Related Corticosteroid Insuffi ciency in the Intensive Care Patient
355
Nonetheless, many subsequent randomized controlled trials and meta-analyses have also supported the conclusion that steroids contribute to more rapid reversal of shock with­out a statistical difference in mortality [ 18 , 20 , 29 – 40 ].

Therapy

Adverse outcomes of steroid therapy are related to the dose and duration of therapy administered. While high-dose glu­cocorticoids are well known to increase the risk of infec­tions, myopathy, wound complications, skeletal wasting, hyperglycemia, and psychosis, low stress dose steroids have been proven safe [ 20 , 34 ]. Interestingly, the downregulation of sepsis-related infl ammation over the short term may actu­ally prove benefi cial to a patient’s resilience to infection
41 ]. In particular, treatment with hydrocortisone may
[ enhance phagocytosis and neutrophil activity. Some studies have even noted a lower risk of hospital-acquired infections with low-dose steroid treatment [
Current practice recommendations are to initiate hydro­cortisone when patients have clinically severe septic shock that is refractory to volume replacement and vasopressor therapy. In critically ill patients without shock, or with hemo­dynamic restoration with vasopressors and fl uids, there is no role for steroid therapy. The use of the cortisol levels and ACTH stimulation test to identify patients for treatment is discouraged (grade 2B [ 14 ]).
Therapy should be initiated with 200 g of hydrocortisone per day (Grade 2C [ 14 , 28 , 30 , 31 , 35 , 36 , 44 , 45 ]. The dos- ing interval may be divided over 6 or 8 h dosing intervals or be given as a continuous infusion. A single prospective trial by Weber-Carstens showed less hyperglycemia and hyperna­tremia when hydrocortisone was given as a continuous infu­sion. This single study led to the 2D recommendation from the surviving sepsis campaign to consider this dosing strat­egy [ 14 , 46 ]; however, further research is needed. The sup- plemental use of fl udrocortisone is not necessary because hydrocortisone has both glucocorticoid and mineralocorti­coid activity [ 14 , 27 ].
Although consensus opinion suggests steroids should be tapered to avoid rebound hypotension and infl ammation, to date the optimal duration of treatment has yet to be deter­mined [ 47 ]. While 5–7 days of therapy is still endorsed by some authors [ 2 , 5 , 48 ], a recent study by Huh et al. showed no difference in outcomes when 3 days of therapy was com­pared to 7 days [ 49 ].
41 , 42 ].

Perioperative “Stress Dose” Steroids

In as much as sepsis and acute illness may precipitate an adrenal crisis, the stress of a surgical procedure may also
unmask adrenal insuffi ciency. For over 50 years, clinicians have administered supraphysiologic steroid doses to patients on long-term steroid therapy. More recently, steroid dosing has been based on the degree of the operative stress. For instance, minor surgery such as an inguinal hernia would be treated with a single dose of 25 mg hydrocortisone intraop­eratively, whereas major operations such as a pancreatico­duodenectomy would be treated with 100–150 mg/24 h hydrocortisone for 3 days.
Recent systematic reviews have challenged the practice of given routine “stress dose” steroids at all. Both a 2008 review by Marik et al. and a 2009 Cochrane review concluded that a patient’s baseline glucocorticoid dose should be continued without administering supraphysiologic doses of “stress” steroids. The caveat to this more relaxed approach, however, is that patients should be monitored and treated with rescue dose steroids should they display unresponsive hypotension in the postoperative period [
50 – 52 ].

Steroids in Acute Respiratory Distress Syndrome (ARDS)

A second patient population that has been intensively eval­uated for a potential role of steroid therapy is those with acute respiratory distress syndrome (ARDS). ARDS repre­sents a potential complication of a group of heterogeneous disease processes. Theoretically, steroids may suppress the degree of fi broproliferative infl ammation seen in some eti­ologies of respiratory dysfunction. However, steroids may be detrimental in ARDS stemming from an infectious pro­cess. Again, the available evidence is fraught with inconsis­tencies in the patient populations studied and the duration of outcome; thus there are confl icting conclusions and rec­ommendations [ 53 ]. Aside from the Meduri trials in 1998 and 2007, most randomized controlled trials have failed to prove a clear mortality benefi t, although secondary out­comes such as duration of mechanical ventilation and reduction of oxygen requirement have shown some prom­ise [ 23 , 54 – 58 ]. Taken together, the available evidence does not support the role of steroids in ARDS, and further inves­tigation is needed.

Summary

In conclusion, CIRCI is a complex, proinfl ammatory state in which there is an inadequate cellular corticosteroid activity for the demand of the physiologic stress suffered by the patient. Despite decades of study, there are still many unan­swered questions regarding the mechanisms, diagnosis, and treatment of CIRCI. At present the best evidence-based rec­ommendations available include:
356
N.N. Saillant and C. Sims
• A clinical diagnosis of CIRCI should be suspected in any critically ill patient who demonstrates hypotension, refractory shock, hypoglycemia, persistent systemic infl ammation, and/or marked eosinophilia.
• ACTH stimulation and random cortisol levels are unreli­able in the diagnosis of CIRCI.
• Hydrocortisone alone (200 mg/day in divided doses or as a continuous infusion) should be administered to patients with septic shock refractory to fl uid resuscitation and vasopressor therapy.
• Patients without shock or with resolution of shock with vasopressor and fl uid therapy should not receive steroids.
• Hydrocortisone should be tapered off after resolution of shock.
• Perioperatively, patients should remain on their pharma­cologic steroid dose.
• “Stress dose steroids” should not be used unless a patient manifests unexplained hypotension in the perioperative period.
• There is no evidence to clearly support steroid therapy in ARDS.

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