Glutamine supplementation of parenteral nutrition in critically ill patients

The role of glutamine in critically ill patients is debatable. Canadian CPGs 2009 recommended that when TPN is prescribed to critically ill patients, parenteral nutrition supplemented with glutamine where available is strongly recommended. However, in a recent update (2013), the committee downgraded the recommendation for IV glutamine to "should be considered". They also strongly recommend that glutamine NOT be used in critically ill patients with multi-organ failure. There are also insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition. Below is the 2013 discussion:
 

It was noted that with the addition of 11 new trials (Tian 2006, Zhang 2007  Ozgultekin 2008, Yang 2008, Eroglu 2009, Perez-Barcena 2010, Andrews 2011, Cekman 2011, Grau 2011, Wernerman 2011 & Ziegler 2012), there were weaker signals for a reduction in overall mortality and  infectious complications and yet a strong treatment effect of IV supplemented glutamine on hospital mortality and ICU and hospital length of stay remained. It was further noted that a few large scale multicenter randomized trials of IV glutamine had failed to demonstrate a convincing positive effect (Andrews 2011, Wernerman 2011, Ziegler 2012).

 

Recent important paper: REDOXs study by the Canadian Critical Care Trials Group. New Engl J Med, 2013, 368:1489-1497.

A Randomized Trial of Glutamine and Antioxidants in Critically Ill Patients. 

Background

Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting.

Methods

In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance.

Results

There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83).

Conclusions

Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure.

 

 Comment: Possible reasons for the different results to previous studies offered by the authors include;

 

1. In this study, combined  enteral and parenteral high doses of glutamine were used in critically ill patients with multi-organ failure. Other studies excluded this group of patients.

2. However, it was felt that the results of this 1223 patient multicentre trial, which suggested a significant safety concern, could not be ignored.

3. Previous studies were smaller and less methodologically robust.

4. The treatment was initiated within 24-hours ICU admission, while other studies used it later.

5. Most patients in this study were enterally fed, other studies they were mainly parenteral nutrition.

 

In summary it appears in ventilated patients with shock/multi-organ dysfunction, the use of early antioxidants is of no benefit, and glutamine may be harmful. Is that enough to close the book on this?

I totally agree with this, since in managing our ICU patients, most of our patients will have more than 2 organ failure and  those with MOF are the ones who carry high mortality. I am not keen to supplement my patients with glutamine either enterally or parenterally.

 

                                                                      xoxoxoxoxoxoxo

 

The earlier study of interest was published in BMJ in 2011 by Andrews et al i.e. SIGNET trial (Scottish Intensive care Glutamine or seleNium Evaluative Trial).

Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients

 

Objective To determine whether inclusion of glutamine, selenium, or both in a standard isonitrogenous, isocaloric preparation of parenteral nutrition influenced new infections and mortality among critically ill patients.

 

Design Randomised, double blinded, factorial, controlled trial.

Setting Level 2 and 3 (or combined) critical care units in Scotland. All 22 units were invited, and 10 participated.

Participants 502 adults in intensive care units and high dependency units for ≥48 hours, with gastrointestinal failure and requiring parenteral nutrition.

Interventions Parenteral glutamine (20.2 g/day) or selenium (500 μg/day), or both, for up to seven days.

Main outcome measures Primary outcomes were participants with new infections in the first 14 days and mortality. An intention to treat analysis and a prespecified analysis of patients who received ≥5 days of the trial intervention are presented. Secondary outcomes included critical care unit and acute hospital lengths of stay, days of antibiotic use, and modified SOFA (Sepsis-related Organ Failure Assessment) score.

Results Selenium supplementation did not significantly affect patients developing a new infection (126/251 v 139/251, odds ratio 0.81 (95% CI 0.57 to 1.15)), except for those who had received ≥5 days of supplementation (odds ratio 0.53 (0.30 to 0.93)). There was no overall effect of glutamine on new infections (134/250 v 131/252, odds ratio 1.07 (0.75 to 1.53)), even if patients received ≥5 days of supplementation (odds ratio 0.99 (0.56 to 1.75)). Six month mortality was not significantly different for selenium (107/251 v 114/251, odds ratio 0.89 (0.62 to 1.29)) or glutamine (115/250 v 106/252, 1.18 (0.82 to 1.70)). Length of stay, days of antibiotic use, and modified SOFA score were not significantly affected by selenium or glutamine supplementation.

Conclusions The primary (intention to treat) analysis showed no effect on new infections or on mortality when parenteral nutrition was supplemented with glutamine or selenium. Patients who received parenteral nutrition supplemented with selenium for ≥5 days did show a reduction in new infections. This finding requires confirmation.

 

 

 

 

Glutamine and Arginine supplementation of enteral feeding in critically ill patients

A variety of enteral feeding formulations were developed for patients with critical illnesses. To the best of our knowledge, no such formulation demonstrated a beneficial effect on clinical outcomes. As a result, disease specific enteral formulation is not recommended over the traditional types of enteral nutrition. However, the enteral nutrition enriched with omega-3 fatty acids may be beneficial to patients with ARDS.

 

Glutamine

Glutamine is a precursor for nucleotide synthesis and an important fuel source for rapidly dividing cells that is rapidly depleted in hypercatabolic patients.

It is nonessential amino acid that can be synthesized from glutamate and glutamic acid by glutamate ammonia ligase. Glutamine is an important fuel source for the small intestine. It was proposed that glutamine is necessary for the maintenance of normal intestinal morphology and function in the absence of luminal nutritients. It was suggested that both glutamine supplemented parenteral and enteral nutrition may prevent bacterial translocation via preservation and augmentation of small bowel villus morphology, intestinal permeability and intestinal immune function. However, it is unclear whether clinically relevant bacterial translocation even occurs in humans, much less whether there is any value in the prevention of such occurrences.

 

Glutamine supplementation of enteral nutrition has been evaluated in more than 30 controlled trials with critically ill patients, most of which had significant methodologic problems or were too small to make definitive conclusions.

Meta-analyses of RCTs that compared enteral nutrition with and without glutamine, there was no difference in mortality or infectious complications. In a recent update (2013), the absence of mortality benefit persisted among patients who received glutamine enriched enteral nutrition (www.criticalcarenutrition.com).

 

Based on 2 level 1 and 7 level 2 studies, enteral glutamine should be considered in burn and trauma patients. There are insufficient data to support glutamine enriched enteral nutrition for routine use in most critically ill patients because clinical trials have not found consistent improvement in clinical outcomes.(Canadian Clinical Practice Guidelines 2013). Given the harm associated with glutamine in patients with multi-organ failure, it is considered unsafe to administer EN glutamine even in burns/trauma patients with MOF (REDOXs trial). There for the CPG strongly against any glutamine to be used in critically ill patients with multi-organ failure.

Glutamine is metabolized by the liver, kidneys and splanchnic tissue into glutamate and ammonia. Accumulation of glutamine and its byproducts may lead to adverse effects such as encephalopathy.

 

 

Arginine

Arginine is considered conditionally essential during critical illness because it is utilized more quickly. It is required for normal immune function and healing. It has improtant roles in nitrogen metabolism, ammonia metabolism and generation of NO. Despite this, aginine enriched enteral nurtition is NOT recommended for routine use in critically ill patients because clinical outcomes have been inconsistent.

Meta-analyses that compared arginine enriched enteral nurtition to standard enteral nutrition in crtically ill patients found no effect on mortality and no effect on infectious complications. These results persisted in the recent update www.criticalcarenutrition.com. Based on 4 level 1 studies and 22 level 2 studies, diet supplemented with arginine and other select nutrients are not recommended to be used for critically ill patients.
Some studies suggested that arginine enriched enteral nutrition was potentially harmful (JPEN 2001).

 

 

 

 

Platelet dysfunction in Uremia

In ICU, sometimes we have to refer our critically ill patients for surgical tracheostomy. The majority of these patients is suffering from MODS which include acute kidney injury. Very often, the level of urea varies from day to day, and also related to the frequency of dialysis in ICU. This is where we have a problem, since quite often the ENT surgeons request for a single digit of urea level. Their concern is bleeding associated with renal failure. Many times the procedure is delayed due to this request. This is what I read from uptodate.com:

The association between renal failure and bleeding was recognized more than 200 years ago. Impaired platelet function is one of the main determinants of uremic bleeding.

Clinical and Lab manifestations

1. Bleeding may involve the skin, oral and nasal mucosa, gingiva, gastrointestinal, urinary tracts and respiratory system. Excessive bleeding may also occur in response to injury or invasive procedures.

2. Although an association between bleeding time prolongation and uremia has long been suggested, there are no good studies demonstrating an increase risk of either spontaneous bleeding or bleeding with a procedure that is associated with prolonged bleeding time among patients with chronic kidney disease.

3. Degree of azotemia (elevation of BUN or creatinine) does not correlate with bleeding risk.

4. Patients may display increased sensitivity to aspirin. The platelet count is usually normal. Generally  levels of circulating coagulation factors are normal and there is no prolongation of the PT or APTT unless there is coexisting coagulopathy.

Pathogenesis - the cause of uremic bleeding is multifactorial.

Causes of platelet impairment include intrinsic platelet defects, abnormal platelet-endothelial interaction, uremic toxins and anemia.

1. The most important factor is platelet dysfunction which is due to decreased platelet aggregation and impaired platelet adhesiveness.Contributing factors extrinsic to platelets include the action of uremic toxins, anemia, increased NO production, von Willebrand factor abormalities, decreased platelet production and abnormal interaction between the platelet and the endothelium of the vessel wall.

2. Uremic toxins:

Consistent with this postulate is the observation that mixing uremic plasma with normal platelets impairs platelet function. However urea is not the major platelet toxin and there is no predictable correlation between the BUN and the bleeding time in patients with renal failure. The addition of urea, guanidinoacetic acid or creatinine to the plasma did not affect platelet function. High levels of guanidinosuccinic acid and methylguanidine have been suggested as potential contributors to uremic platelet dysfunction, likely through simulation of NO production.

3. Anemia

Is common in patients with CKD and is primarily due to decreased renal erythropoietin production. Correction of anemia with blood transfusions or erythopoietic stimulating agents often improves platelet dysfunction. It has been proposed that rheologic factors play an important role in the overall relationship between anemia and platelet function.

4. Nitric oxide

NO is an inhibitor of platelet aggregation that is produced by endothelial cells and platelets. Studies have shown that platelet NO synthesis is increased, may be due to elevated levels of guanidinosuccinic acid (uremic toxin).

Treatment:

No specific therapy is required in patients without bleeding even in the setting of severe azotemia. Correction of platelet dysfunction is warranted in patients who are actively bleeding or who are about to undergo a surgical procedure. It is important to identify any sources of bleeding.

 

A number of modalities to improve platelet function and reduce bleeding, which vary in their onset and duration of action.

 

1. Dialysis:

Hemodialysis can partially correct the bleeding in about two thirds of uremic patients. It should be done without systemic anticoagulation.

2. Desmopressin

It is the simplest and most rapidly acting of acute treatment for platelet dysfunction in uremic patient. dDAVP is effective in at least one-half of patients and appears to act by increasing the release of large factor VIII: von Willebrand factor multimers from endothelial cells. Other factors may include increases in platelet membrane glycoprotein expression. dDAVP can be given intravenously at a dose of 0.3 mcg/kg (in 50 ml of saline over 15 to 30 minutes if IV) or 3 mcg/kg if intranasally. The improvement in bleeding time begins within one hour and lasts 4 to 8 hours. Tachyphylaxis typically develops after the second dose, perhaps due to depletion of endothelial stores of the factor VIII: von Willebrand factor multimers. Reduced urine volume and hyponatremia may occur in patients who have urine output.

 

3. Correction of anemia

Raising the Hb to about 10g/dL or higher will reduce the bleeding time in many patients, occasionally to a normal level. This can be achieved by RC transfusions or via administration of recombinant erytrhopoietic stimulating agents (ESAs). The improvement in platelet function persists for as long as the Hb remains elevated. ESAs may also have a direct beneficial effect on platelet function.

4. Estrogen
Most chronic control of bleeding can be achieved in many uremic patients by the administration of conjugated estrogens. The long term use is limited by estrogen related side effects. The mechanism is not well understood but may be due to decreased generation of NO.

5. Cryoprecipitate
The infusion of cryoprecipitate (10 units intravenously every 12 - 24 hours) can shorten the bleeding time in many uremic patients. The improvement in BT begins within one hour and lasts 4-24 hours;  it is presumably mediated by the presence in cryoprecipitate of a substance that enhances platelet aggregation, such as factor VIII: von Willibrand factor multimers. The potential risk of infectious complications of this modality limit its use to patients with life threatening bleeding who are resistant to treatment with dDAVP and blood transfusions.

In my opinion, the surgeons (esp ENT surgeon in my case) should understand about the multifactoral causes of platelet dysfunction in uremia. There is no correlation in between the  value of BUN and the risk of bleeding. If the patient is on regular dialysis, have a good Hb and no evidence of spontaneous bleeding there are no reasons to postpone the tracheostomy. If intermittent HD is done, anticoagulation should be avoided especially after the procedure. I should do more PDT in my ICU to overcome this problem.