Enteral nutrition and parenteral nutrition for septic shock: are they equivalent?

Translated by Fu Yuxin, Department of Critical Care Medicine, Fourth Hospital of Hebei Medical University, Zhu Guijun, reviewed the critical illness practitioner translation group.
Purpose The current review focuses on the latest clinical evidence and the latest guideline recommendations.
It is about enteral nutrition and intestinal nutrition for adults with severe septic shock.
Clinical evidence and guidelines update on external nutrition.

The largest multicenter randomized controlled trial found recently showed that for shock patients with mechanical ventilation, the 28-day and 90-day mortality, infection incidence, and length of stay in hospital are not important.

However, enteral nutrition is associated with lower intake of micronutrients, and the incidence of hypoglycemia and moderate to severe gastrointestinal complications is significantly higher.

The integration of these studies into a recent meta-analysis confirms that it is inconsistent or questionable that the nutritional supply pathway has no effect on mortality and the interaction with (infection) morbidity.

Summary In critically ill patients, the powerful model of using enteral nutrition instead of parenteral nutrition has been challenged.

Therefore, the latest guidelines recommend stopping enteral nutrition for patients with uncontrolled shock.

However, it is still unclear whether parenteral nutrition is beneficial to patients with shock, but in the case of fewer gastrointestinal complications, the benefits are conceivable.

So far, there are no indications for parenteral nutrition in these patients.

Taking into account the recent scientific evidence, specific guidelines and recommendations, and expert opinions, we have proposed a clinical process that may help to decide the feeding method of severely ill patients with shock.

Key point 1.
Metabolic (in) adaptation plays an important role in the host response caused by sepsis and the resistance to acute systemic infections.

2.
The way of nutrition supply has no effect on the mortality of critically ill adults suffering from (septic) shock. 3.
The physiological principle of early enteral nutrition on intestinal protection has not been confirmed by randomized controlled trials.
However, a controversial meta-analysis showed that the benefits of reducing the incidence of infection complications are questionable.

4.
Complete parenteral nutrition can reduce the incidence of moderate to severe gastrointestinal complications and the risk of hypoglycemia.

5.
The latest guidelines consistently recommend avoiding enteral nutrition for patients with hemodynamic instability.

Once the shock is under control, small doses of enteral nutrition can be started.

However, so far, it is not clear whether well-designed early parenteral nutrition will be superior to the fasting state of patients with uncorrected shock; in addition, the potential benefits of parenteral nutrition have not been considered in these recommendations.

Preface According to the sepsis 3.
0 standard, septic shock is defined as "a subset of sepsis, and its severe circulatory, cellular and metabolic abnormalities are related to increased mortality.
"
This updated definition emphasizes the widely recognized pathophysiological importance of metabolic disorders caused by sepsis.

Typical metabolic disorders include changes in energy expenditure, stress hyperglycemia, acute muscle protein breakdown, increased circulation of endogenous amino acids, accelerated liver glucose production, and insulin resistance.

The development of glucose metabolism disorders and insulin resistance play an important role in the process of hyperglycemia caused by sepsis, which is the body's adaptive host response to acute systemic infections.

Recent evidence indicates that maintaining adequate hepatic glucose production not only depends on the supply of gluconeogenic substrates, but also involves more subtle mechanisms such as the induction of iron-chelated ferritin H chains.

Medical Nutrition Therapy (MNT) includes multiple components such as time, substrate delivery route (intestinal and parenteral), quantity and composition of macronutrients and micronutrients.

MNT is believed to significantly interfere with this endogenous metabolic response, depending on the stage of the disease and the nature of the triggering homeostasis disorder, which may affect the clinical outcome.

For more than ten years, the enteral route is obviously superior to the parenteral route, which has been one of the mainstream of various expert opinions and guidelines.

However, this model has recently been challenged.

The purpose of this review is to provide an up-to-date review of the trials and recommendations conducted in the past 18 months on the risks and benefits of enteral and parenteral nutrition delivery in patients with severe septic shock.

The (pathological) physiological changes of shock: Severe diseases related to medical nutrition treatment can disrupt the mutually beneficial balance between the intestinal epithelium and the microbiota, which in turn leads to the generation and continuation of multiple organ dysfunction.

In sepsis, the release of cytokines directly hinders the function of intestinal muscle cells, inhibits enteric neuromuscular transmission, causes gastrointestinal hormone imbalance, and causes intestinal edema.

In addition to these "intrinsic" mechanisms, the main "external" risk factor for gastrointestinal dysfunction during shock is the use of vasoconstrictive drugs, such as catecholamines or vasopressin.

Although shock itself can cause blood to redistribute from the intestine, frequent use of vasoactive drugs, especially a1 activity or v1a activity, enhances visceral vasoconstriction, which may vary depending on the type of shock or vasoactive agent used.

In addition, the effect of vasoactive substances on the total blood flow of the internal organs may not be representative of the changes in the internal organs of the individual.

In the acute phase of critical illness, the decision to choose the enteral route or the parenteral route mainly depends on the function of the gastrointestinal tract, but the individual's metabolic tolerance should determine the intake of macronutrients.

Based largely on experiments in rodents, the benefits of enteral nutrition are related to various positive physiological (non-nutritive) effects on gastrointestinal function, including maintaining intestinal structure, function, and integrity of intestinal hormones.
The mechanism of reducing oxidative stress in the intestine.

Therefore, early enteral nutrition after hemodynamic stabilization is considered to improve the prognosis by "stabilizing" the intestine as an organ dysfunction caused by sepsis.

However, the enthusiasm for enteral nutrition largely ignores the fact that the gastrointestinal tracts of rodents and humans are very different.

In addition, the parenteral route of exogenous substrate supply is also conducive to intestinal health: parenteral nutrition supports the renewal rate of intestinal cells, increases the rate of intestinal protein synthesis, and reduces the rate of apoptosis by directly providing matrix to the crypts.

In addition, even after several weeks of complete parenteral nutrition, no significant changes in human intestinal protein content, intestinal cell proliferation, or microvilli morphology were observed.

On the contrary, active enteral nutrition can neither prevent a significant increase in liver fat content, nor can it prevent continued protein catabolism.

However, regardless of the nutrient supply route, the quantity and type of macronutrients provided may be important for the activity of autophagy and inflammatory response.

Table 1 summarizes the advantages and disadvantages of enteral nutrition and parenteral nutrition in patients with severe combined (septic) shock.

Observational studies In the past 12 to 18 months, three observational studies have been published to explore the importance of enteral nutrition in patients with impaired hemodynamics.

In a single-center retrospective study, Merchan et al.
evaluated variables that may have an important impact on enteral nutrition tolerance, including 120 ICU patients with septic shock and vasoactive drug support.
These patients were in the initial The hemodynamics is stable after fluid resuscitation.

Patients with the following manifestations, including increased residual gastric volume, vomiting, abnormal abdominal imaging, or mesenteric ischemia, are classified as enteral nutrition intolerance; 38% of patients have experienced one or more of these complications.

The most common cause of enteral nutritional intolerance is that the residual gastric volume exceeds 250 ml.

The occurrence of mesenteric ischemia has not been reported.

A multivariate analysis showed that patients with septic shock who received enteral nutrition within 48 hours and required a dose of norepinephrine of 0.
14 mg/kg/min or less were more likely to tolerate enteral nutrition.

The authors concluded that enteral nutrition can be safely applied to such patients.

In a recent multi-center retrospective database analysis from 2010 to 2016, Ohbe et al.
evaluated the results of early and delayed enteral nutrition in patients with cardiogenic or obstructive shock that require (VA-ECMO) treatment.

Early enteral nutrition is defined as the start of enteral nutrition 2 days or less after the initiation of VA-ECMO.

The final analysis included 1769 patients, of which 1549 (88%) received late enteral nutrition (defined as VA-ECMO for more than 3 days) and 220 early enteral nutrition.

Using a marginal structure model to adjust baseline and time-dependent confounding factors, "early" enteral nutrition can reduce hospitalization and 28-day mortality compared with "delayed" enteral nutrition.

No differences were found in infectious complications and gastrointestinal ischemic events.

In another study, Ohbe et al.
used the same database and design to compare shock patients (requiring low dose (<0.
1mg/kg/min), medium dose (0.
1~0.
3mg/kg/min) and high dose ( 0.
3mg/kg/min) norepinephrine maintenance), early mechanical ventilation (2 days after the start of mechanical ventilation) and late enteral nutrition in mechanical ventilation.

In the propensity score matching analysis, 5969 patients, 2162 patients and 477 patients in the low-dose, medium-dose and high-dose norepinephrine groups were included.
Compared with late enteral nutrition, the 28-day mortality rate of early enteral nutrition was significant.
Significant reduction in the low-dose and medium-dose norepinephrine group, but in the high-dose norepinephrine group, there was no significant difference between the groups.

However, these studies have received a lot of criticism because they only compared severe low-calorie nutrition (late) and moderate low-calorie nutrition (early).
The benefits of "early" may only be related to higher calorie intake in the acute phase.
It has nothing to do with the way of nutrition supply.

In addition, there is no statistical method that can completely eliminate the "indicative bias" in observational studies.

NUTRIREA-2 Randomized Controlled Trial NUTRIREA-2 is a large, multi-center, randomized, controlled study, non-blinded parallel group trial that evaluates early first-line enteral nutrition or parenteral nutrition on 2410 patients with severe mechanical ventilation shock (its definition For the use of vasoactive therapy (epinephrine, dobutamine or norepinephrine) to treat shock) the impact of mortality.

After enrollment, patients were randomly assigned to receive complete enteral nutrition or complete parenteral nutrition for 7 days.
The calorie goal from day 1 to day 7 was 20-25kcal/kg, and the calories from day 8 until tracheal intubation was removed.
The target is 25-30kcal/kg.

For patients randomized to receive early enteral nutrition therapy, parenteral supplementation is not allowed.

The individual's calorie goal determines the amount of nutrition for patients in the enteral nutrition group, while patients in the parenteral nutrition group only receive nutrition through the central vein for at least 72 hours.

If the patient’s hemodynamics is stable (defined as at least 24 hours without vasoactive drug support, arterial blood lactic acid concentration is less than 2 mmol/l), allow 72 hours to reach the pre-set calorie target calories Converted to enteral nutrition.

If the hemodynamics is stable and sustained, parenteral nutrition can last up to 7 days.

At the latest on the 8th day, regardless of the hemodynamic status, the patient should be switched to enteral nutrition.

The baseline variables were well balanced between the groups.
The average SOFA score was 11 points, the average lactate concentration was 3.
8 mmol/l, and the median norepinephrine dose was about 0.
5 mg/kg/min (present in 80% of patients at baseline ), reflecting a higher baseline disease severity.

Sepsis is the root cause of shock in two-thirds (62.
5%) of patients.

Both groups started using MNT 16 hours after intubation, and the median time of receiving intervention was generally shorter (parenteral nutrition 4 days, enteral nutrition 6 days).

4% parenteral nutrition group and 6% enteral nutrition group overlap.

The daily calorie intake of the two groups was close to 20-25 kcal/kg/d, while the macronutrient intake of the enteral nutrition group was slightly lower.

After 2000 patients were enrolled, the study was terminated early because the external safety committee believed that enrolling the remaining 854 patients was unlikely to significantly change the results.

Taking 28-day mortality as the main outcome, the incidence of infection complications, duration of organ failure severity, life support time, ICU or hospitalization days, and 90-day mortality were pre-specified secondary outcomes, and no significant differences were found.

The authors concluded that in the acute phase of critical illness, if the initial circulatory failure is only moderate, early parenteral nutrition is basically the same as early enteral nutrition.

This result is consistent with the results of the calorie test for non-shock patients published in 2014.

However, because enteral nutrition increases the frequency of moderate gastrointestinal complications, including vomiting (34% vs.
24%) and diarrhea (36% vs.
33%, P = 0.
009), as well as severe intestinal ischemia Gastrointestinal complications (2 vs.
1%, P 0.
007) and colon pseudo-obstruction (1 vs.
<1%, P = 0.
04).

In addition, more patients in the enteral nutrition group had hypoglycemia (2vs.
1%, P<0.
01); the initial lactic acid concentration increased and was comparable, but it is expected that the proportion of enteral nutrition returning to normal in the parenteral nutrition group was lower than that in the parenteral nutrition group.
Parenteral nutrition group (62% vs.
66%, P 0.
03).

The frequency of vomiting and hypoglycemia in the enteral nutrition group also increased significantly in the CALORIES trial.

In the early stages of the study, the NUTRIREA-2 and CALORIES trials were very effective in obtaining relatively high calorie intake through both methods.

In the absence of additional calorie intake, almost all the following days, the calorie goal was reached.

Therefore, the higher proportion of patients with moderate gastrointestinal complications during enteral nutrition may be due to the higher intake of enteral macronutrients in the early acute phase.

The low rate of normalization of lactic acid may be due to mismatched mucosal oxygen supply (decreased blood flow redirection caused by catecholamines) and oxygen demand (increased digestive oxygen consumption stimuli caused by nutrition).

Intestinal macronutrient absorption caused by gastrointestinal dysfunction may make patients more prone to hypoglycemia.

In addition, sepsis's inflammatory response, gastrointestinal edema, and changes in visceral blood flow may lead to severe gastroplegia and reduce gastrointestinal motility during subsequent vomiting.

Meta-analysis Three meta-analyses studied the effects of enteral nutrition or parenteral nutrition, or a combination of the two, on the clinical outcomes of adult ICU patients.

A detailed description of these meta-analyses is shown in Table 2.

Lewis et al.
evaluated the effects of complete enteral nutrition and complete parenteral nutrition, the combination of complete enteral nutrition and enteral nutrition and parenteral nutrition on mortality, the number of ICU-free days up to day 28, and adverse events. Zhang et al.
analyzed 23 studies (NUTRIREA-2 and the CALORIES trial) to assess the overall impact of complete enteral nutrition and complete parenteral nutrition on mortality (primary outcome) and several clinical secondary outcomes in critically ill patients.

Shi et al.
studied the effects of combined application of enteral nutrition and parenteral nutrition and complete application of enteral nutrition on hospital mortality (primary outcome) and various secondary outcomes in critically ill patients.

In essence, only the meta-analysis of Lewis et al.
and Zhang et al.
directly compares complete enteral nutrition and complete parenteral nutrition (thereby analyzing the "real" effects of nutritional pathways).

Neither meta-analysis found an effect on the mortality endpoint.

Although Lewis et al.
concluded that there is insufficient evidence to show that nutritional supply pathways are important for secondary outcomes.

Zhang et al.
report that enteral nutrition reduces the frequency of blood infections (BSI) and length of hospital stay, but it also increases the risk of gastrointestinal complications.

For example, the survey results on the frequency of BSI are seriously biased; in order to analyze the latter outcome variable, the authors included 14 studies, three of which were conducted on patients after severe head injury, and one of the studies was on major elective dates.
The immunonutrition test performed by patients after surgery, the other two studies provided almost twice the calories during parenteral nutrition; individual studies have shown that severe burn patients in Vietnam (average daily intake of 40 kcal/kg calories) or severe burns in China Patients with acute pancreatitis (30-35 kcal/kg calories per day) have significant effects; none of the studies were blinded, and 11 studies were single-center studies, with less than 100 patients randomly selected.

The last three characteristics are known to cause significant overestimation of the effect size (each ranging from 10% to 25%).

In view of these limitations, our conclusion is that nutritional pathways have no effect on mortality.

Although complete parenteral nutrition is associated with fewer moderate to severe gastrointestinal and metabolic adverse events, the beneficial effect of the enteral route on the incidence of infectious diseases is still inconclusive.

Instead, they seem to be related to the intensity of macronutrient intake, rather than nutritional pathways (earlier meta-analysis has shown).

All of the above meta-analysis performed pre-determined subgroup analysis, but none specifically targeted (septic) shock patients.

The updated guidelines recommend that in 2016, the guidelines and enteral nutrition recommendations of the Institute of Critical Care Medicine and the American Society of Parenteral Nutrition (according to expert opinions), enteral nutrition should be retained until the patient is "completely resuscitated", and if hemodynamics are present Damage or instability, the enteral route should not be used.

This recommendation applies to patients with hypotension who are starting vasoactive or inotropic support or must be increased to maintain adequate perfusion pressure or cardiac output.

In patients supported by low and stable doses of vasoactive drugs, “enteral nutrition may need to be provided with caution”, but if early symptoms of intestinal ischemia occur (abdominal distension, symptoms of paralytic intestinal obstruction, vomiting/increased gastric residue, or inclusion of lactic acid Acidosis, including acid-base disorders), should immediately stop providing enteral nutrition.

Patients with septic shock should also retain enteral nutrition before the resuscitation is completed; for patients in the acute stage of septic shock, complete parenteral nutrition or combined enteral nutrition is not recommended.

The Save Sepsis Campaign made the same recommendation.

The European Association of Intensive Care Medicine (ESICM) 2017 "Early Enteral Nutrition Practice Guidelines for Critically Ill Patients" recommends delaying enteral nutrition therapy for patients with uncontrolled shock who receive vasoactive drugs or cardiotonic drugs and perfusion is up to standard.

Once the shock is controlled, low-dose enteral MNT should be started immediately.

Since early enteral nutrition is the focus of this guide, there is no recommendation on the comparison of enteral nutrition and parenteral nutrition, except for the use of early enteral nutrition instead of early parenteral nutrition or delayed enteral nutrition recommendations in general critically ill patients.
.

Recently, the European Society of Clinical Nutrition and Metabolism (ESPEN) updated their guidelines on MNT in critically ill patients.

The ESPEN guidelines cited enteral nutrition taboos defined by the ESICM expert group, including shock, uncontrolled hypoxemia, acidosis, and intestinal ischemia.

ESPEN recommends not to use enteral nutrition when the shock is not controlled and the hemodynamic and tissue perfusion goals are not met.

According to the ESICM guidelines, low-dose enteral nutrition is recommended only if the shock is controlled by fluids and vasoactive drugs.

Emphasize the need to closely monitor gastrointestinal function during enteral nutrition to avoid missing signs and symptoms of intestinal ischemia.

The results of NUTRIREA-2 may have influenced the formulation of the latter recommendation.

It is worth noting that ESPEN does not clearly point out the role of (early) parenteral nutrition and early enteral nutrition in patients with shock.

Table 3 summarizes relevant guidelines for MNT in patients with hemodynamic instability/(septic) shock.

Conclusion The physiological principles of intestinal protection caused by enteral nutrition and subsequent avoidance or reduction of organ dysfunction caused by sepsis-according to the phrase "use it (intestine) or liberate it"-are mainly based on rodents experiment of.

This effect has not been proven by methodologically reasonable and sufficiently powerful controlled trials or meta-analysis.

The hypothesis that the positive nutritional effect of early "low-dose" enteral nutrition is better than fasting or early parenteral nutrition has not been verified.

In contrast, two large multi-center trials conducted in severe patients with or without shock consistently showed that the parenteral route in the acute phase is equivalent and mildly low-calorie macronutrient intake (80-90% calorie target) The premise is that it has clinical advantages in terms of metabolism and gastrointestinal complications.

Therefore, are the enteral and parenteral routes equivalent in patients with septic shock? The answer to this question depends on the clinical endpoint goal.

Although the answer to mortality is yes, for some diseases, the answer is no.

In terms of metabolism (less hypoglycemia) and gastrointestinal endpoints, parenteral routes have obvious advantages, and in terms of the incidence of infectious complications, the evidence supporting enteral nutrition is inconsistent.

In view of this "change of approach", we provide a clinically-oriented process on how to perform MNT in the acute phase of septic shock patients (Figure 1).

Finally, we firmly believe that the amount and composition of macronutrients and their exposure time (relatively shorter in the NUTRIREA-2 and CALORIES trials) are clinically more relevant than the nutritional supply route.

To be effective, MNT should basically respect the patient's individual metabolic tolerance in the acute phase of sepsis.

Source: Critical Care Medicine END Please long press the picture below to identify the QR code.
Pay attention to dopamine.
I am the last dopamine, recording the real voice of the world.

Some pictures and music come from the Internet.
If there is any infringement, please contact us in time.

Copyright and cooperation WeChat: dba0604 Contribution email: last-dopamine@foxmail.
com I used a stethoscope to measure the lives of those who met each other in peace, and the lives that passed away in my hands were dripped with tears piled up in the corners of my eyes.
Explained to me the meaning of life