Page 844 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 64: Sepsis, Severe Sepsis, and Septic Shock 575

(CVVHD), continuous veno-venous hemodiafiltration (CVVHDF), The first multicenter randomized controlled trial to evaluate inten-
slow continuous ultrafiltration (SCUF), and sustained low-efficiency sive insulin therapy in severe sepsis patients was recently published, the
dialysis (SLED). We mention these modalities briefly, from the perspec- Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis
tive of sepsis patient management. (VISEP). The trial was terminated earlier than planned due to an
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Conventional hemodialysis may be used in patients with sepsis, increased number of hypoglycemic events in the intensive insulin group
either through an existing vascular access (fistula or graft) or via compared to the conventional therapy group (12.1% vs 2.1%; p <0.001).
a central venous catheter, but the higher average flow rates and However, of the 537 patients that were randomized to receive intensive
potential for adverse hemodynamic consequences limit the applica- or conventional insulin therapy, there was no significant difference
tion of HD in critically ill patients. CVVH, sometimes referred to as between the two groups in 28-day mortality or in organ dysfunction.
continuous renal replacement therapy (CRRT), requires placement of Similar to VISEP, the international multicentered GLUCONTROL trial
a central venous catheter and most systems require anticoagulation comparing intensive insulin therapy to normoglycemia (140-180 mg/dL)
with heparin or citrate. Typically the dialysate has lactate-buffered was stopped early due to a high rate of hypoglycemia with insulin therapy
solution but in the case of severe lactic acidosis (serum lactate greater and without any mortality benefit. The largest intensive insulin
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than 5 mmol/L), bicarbonate solution is used. The lower flow rates therapy trial, the Normoglycemia in Intensive Care Evaluation-Survival
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of CVVH are less prone to cause hemodynamic instability than HD, Using Glucose Algorithm Regulation (NICE-SUGAR) study, evalu-
and sodium removal can be separated from water removal in this ated 6000 critically ill patients and found that intensive glucose control
system. CVVHD is similar to CVVH; it removes waste by diffu- (target range 80-108 mg/dL) resulted in increased mortality compared
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sion only and can be coupled with fluid removal (ultrafiltration). to conventional glucose control (target range <180 mg/dL) (27.9% vs
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CVVHDF is a combination of dialysis and hemofiltration. SCUF 24.9%, respectively; p = 0.02). Subgroup analyses suggested no sig-
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only permits ultrafiltration and does not remove waste. SLED can nificant difference in treatment effect for patients with and without
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be done either intermittently or continuously and its efficiency is severe sepsis (p = 0.93). Additionally, severe hypoglycemia (defined as
comparable to HD and CVVH with similar hemodynamic tolerance a blood glucose <40 mg/dL) was greater in those undergoing intensive
as other forms of CRRT. insulin therapy versus conventional therapy (6.8% vs 0.5% respectively;
There is no consensus regarding which CRRT modality is superior in p <0.001). 205
sepsis. Currently, there is no evidence that CRRT decreases mortality, Taken together, intensive insulin therapy has no clear beneficial effect
improves kidney function, or decreases length of hospital stay compared among patients with sepsis, who may be a higher than average risk for
to intermittent dialysis. Clinicians need to decide which modality will insulin-related complications such as hypoglycemia. Thus, while the
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be most tolerated by the critically ill patient. optimal target glucose range remains uncertain for sepsis patients,
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■ MOBILITY current guidelines recommend maintaining glucose levels less than
150 mg/dL using intravenous insulin therapy in ICU patients with severe
The nascent field of acute ICU rehabilitation and mobility has begun sepsis and hyperglycemia. 91
to address the frequent occurrence of ICU myopathy that occurs after ■
prolonged hospital stay and is particularly frequent in patients with VTE AND STRESS ULCER PROPHYLAXIS
sepsis. The posthospitalization debility has severe consequences to Prophylaxis for deep venous thrombosis (DVT) has been proven ben-
patients after discharge, where family members may bear the burden eficial for critically ill patients in many randomized placebo controlled
to care for the debilitated patient. Several studies have shown that early trials. 207-213 A recent meta-analysis comparing unfractionated heparin
mobilization, even for those patients on ventilators, can be achieved (UFH) twice daily to three times daily showed that UFH three times daily
safely with a dedicated ICU team. More important, these early studies seemed to be more efficacious in preventing clinically relevant venous
suggest that early mobility, when combined with breaks in sedation, may thromboembolism (VTE) ; however, physicians should evaluate the
214
reduce hospital length of stay and ICU-related delirium, and increase underlying risk of VTE and bleeding to individualize therapy. Mechanical
the likelihood of return to independent function. 199-201 Although early methods such as intermittent compression devices and compression
and aggressive physical therapy and early mobilization in the ICU are stockings are recommended when anticoagulation is contraindicated or
not part of current sepsis management guidelines, these data suggest in addition to anticoagulation in high-risk patients. 212,213,215 DVT prophy-
important benefits may be accrued using a multidisciplinary team laxis is therefore strongly recommended in patients with severe sepsis. 91
approach to ensure safety. Sepsis is often associated with risk factors for the development
■ GLYCEMIC CONTROL of stress ulcers including mechanical ventilation, coagulopathy, and
hypotension. Although no clinical outcome study has been performed
Van den Berghe and colleagues conducted a landmark randomized specifically regarding stress ulcer prophylaxis in severe sepsis patients,
single center trial by randomizing approximately 1500 cardiac surgi- numerous studies have shown that stress ulcer prophylaxis reduces the
cal patients to receive either intensive insulin therapy (maintaining incidence of gastrointestinal (GI) bleeding in subgroups of critically ill
blood glucose levels between 80 and 110 mg/dL) or more conventional patients, including patients with severe sepsis. 216-219 However, controver-
treatment (maintaining blood glucose between 180 and 200 mg/dL sies exist for the use of stress ulcer prophylaxis as there has not been a
and infusion of insulin only for blood glucose > 215 mg/dL) in addi- demonstrated decrease in mortality 220,221 and use of stress ulcer prophy-
tion to high intravenous glucose loads (200-300 g per 24 hours). laxis has been implicated in the development of VAP, so the benefit
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Intensive insulin therapy reduced ICU mortality (8.0% vs 4.6%; of preventing an upper GI bleed should be weighed against the risk of
p <0.04), with a greater effect in patients that remained in the ICU for inducing pneumonia. However, despite these controversies, stress ulcer
greater than 5 days (20.2% vs 10.6%; p = 0.005). However, a subse- prophylaxis using H blockers should be given to all patients with severe
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quent study conducted in medical ICU patients found that intensive sepsis to prevent an upper GI bleed. 91
insulin therapy did not improve survival despite shortened ICU and
hospital length of stay, earlier weaning from the ventilator, and less NEW DIRECTIONS
kidney injury. Intensive insulin therapy reduced in-hospital mortality
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in those patients who stayed in the ICU for greater than 3 days (52.5% vs The past decade has seen tremendous advances in the field of sepsis,
43.0%; p = 0.009), but increased mortality in those patients who stayed from better understanding of epidemiology and pathophysiology to
in the ICU for less than 3 days. Furthermore, intensive insulin protocol the development and market availability of new therapies. Despite this
resulted in high rates of hypoglycemia (18%). 202,203 progress, there is much work to be done in order to ensure the optimal

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