50. Good Housekeeping

 WILKINSON & SHEERIN 

 Good Housekeeping: STRESS ULCER and VTE prophylaxis 

Andy Wilkinson and Eamonn Sheerin are registrars currently working in ICU in Sydney. They are relatively new to ICU and have been looking into why we do some of what we do on our daily ward rounds.

This podcasts focuses on ways of remembering the important things that can be forgotten, and in particular stress ulcer prophylaxis and venous thromboembolism (VTE) prophylaxis.

Click READ MORE for the podcast, and links...

Listen to the talk here:

For more on FAST HUG IN BED Please look here

The alternative (more hardcore) version is DANISH BUG FEST

D e-escalte - especially anti-biotics, review other meds that may no longer be needed

A nalgesia - Is that why they're hypertensive & tachycardic?

N asogastric Tube - need one? Need to remove one?

I ndwelling Catheter - Pull it out ASAP

S edation - What's the RASS? Can you cut back?

H ead of bed 30 degrees - Not amazing evidence but we do it.

B owel care - Many patients need aperiants. Look for, prevent and investigate diarrhoea.

U lcer prophylaxis - listen to the podcast!

G lycaemic control - here's a podcast & review

F eeding and Fluids - are you feeding? what are you giving? should you be giving less fluid?

E nvironment - think delirium avoidance. Prevention is better than cure! What would you want in ICU?

S kin - pressure areas can get infected; rashes may be significant.

T hromboembolism prophylaxis - listen to the podcast!

Notes to go with the Eamonn's Stress Ulcer Prophylaxis section:

Q1. What are we trying to prevent?

Stress ulcers are gastric mucosal erosions that can develop in patients with a serious illness or severe injury. Unlike peptic ulcers, which tend to develop in the antrum or duodenum, stress-related mucosal injuries typically occur in the acid-producing areas of the stomach (i.e., corpus and fundus). Stress ulcers, unlike peptic ulcers, tend to cause gastrointestinal (GI) bleeding and are not associated with abdominal pain. The mucosal changes of stress-related mucosal injury mainly involve small erosions that do not lead to bleeding but may develop into deeper ulcers, which cause bleeding. 

Endoscopy performed within 72 hours of a major burn or cranial trauma reveals acute mucosal abnormalities in greater than 75 percent of patients[i].  Incidence of clinically significant bleeding range from 1.5 to 8.5 percent among all ICU patients[ii], but may be as high as 15 percent among patients who do not receive stress ulcer prophylaxis[iii].

Q2. Which pharmalogical agents should we use?

• H2 blockers, PPIs, and antacids all reduce the frequency of overt GI bleeding in ICU patients compared to placebo or no prophylaxis

• H2 blockers versus PPI – A meta-analysis of 13 randomized trials (1587 patients) compared stress ulcer prophylaxis with a PPI to prophylaxis with an H2 blocker. It found less GI bleeding among those who received a PPI (1.3 versus 6.6 percent, odds ratio 0.30, 95% CI 0.17-0.54). There was no difference in mortality or the incidence of nosocomial pneumonia[iv].

Q3. Who should we be giving prophylaxis to?

A multicenter prospective cohort study of 2252 ICU patients identified two major risk factors for clinically important GI bleeding (defined as overt GI bleeding leading to hemodynamic deterioration or requiring blood transfusion)[v] due to stress ulceration:

• Mechanical ventilation for more than 48 hours (odds ratio 15.6)
• Coagulopathy (odds ratio 4.3) – defined as INR over 1.5, platelets < 50 or a partial thromboplastin time (PTT) >2 times the control value

The incidence of clinically important GI bleeding among patients with one or both of these risk factors was 3.7 percent. In patients with neither RF the incidence was 0.1 percent, and the study concluded that prophylaxis was not indicated in these patients.

The American Society of Health-System Pharmacists has developed one of the most comprehensive evidence-based guidelines for SUP.[vi]

These are summarised here.

Enteral nutrition alone may reduce the risk of overt GI bleeding due to stress ulceration and that stress ulcer prophylaxis may be ineffective or harmful among patients who are receiving enteral nutrition:

• Enteral nutrition alone may reduce the risk of overt GI bleeding due to stress ulceration. In one observational study performed using data from a randomized trial, enteral nutrition independently reduced overt GI bleeding (relative risk 0.30, 95% CI, 0.13-0.67) in 1077 critically ill patients who were mechanically ventilated for more than 48 hours[vii].

• Pharmacological stress ulcer prophylaxis may be ineffective or harmful among patients who are receiving enteral nutrition: A quantitative systematic review of randomized trials comparing H2 blockers to placebo for the prevention of stress ulceration found that the effect of the H2 blockers varied according to whether the patients were receiving early enteral nutrition[viii]. Among patients not receiving early enteral nutrition, H2 blockers reduced the incidence of GI bleeding and had no significant effect on mortality or the rate of hospital-acquired pneumonia. Among patients receiving early enteral nutrition, however, H2 blockers increased mortality and the incidence of hospital-acquired pneumonia, without reducing the rate of GI bleeding. This systematic review had several important limitations. Among the limitations, it included both patients who are at high risk and low risk for stress ulceration. Thus, it is possible that the harmful effects of prophylaxis seen among patients receiving enteral nutrition were due to unnecessary prophylaxis in low risk patients, rather than a more general harmful effect among all patients.

 It is uncertain this is sufficient to justify withholding stress ulcer prophylaxis from patients who are at high risk for gastrointestinal bleeding even if they are receiving enteral nutrition.

Q4. Are there any potential harms of prophylaxis?

Interstitial nephritis

• The incidence of acute interstitial nephritis related to PPIs remains uncertain, but it is thought to be relatively uncommon. During a 22 month period, six cases of acute interstitial nephritis associated with PPIs, proved by biopsy, in a renal centre serving a population of 1.1 million people. Treatment consists of discontinuation and steroids. Ranitidine has a lower incidence.

C. Difficile

• ^§A recent analysis of data from patient discharges from a tertiary medical center over a 5-year period found that the risk of nosocomial CDI was positively correlated with the level of acid suppression and was highest in patients receiving PPI therapy more than once daily, suggesting a dose-response effect on the risk of nosocomial CDI[ix].

Nococomial pneumonia

• Meta-analyses suggest that prophylactic agents that increase gastric pH may increase the frequency of nosocomial pneumonia compared to agents that do not alter gastric pH (eg, sucralfate) 
• As an example, a trial that randomly assigned 1200 mechanically ventilated patients to receive either an intravenous H2 blocker or sucralfate found that ventilator-associated pneumonia was more frequent in the H2 blocker group, although the difference was not statistically significant (19 versus 16 percent, RR 1.18, 95% CI 0.92-1.51)[x].
• A potential mechanism for prophylaxis-related nosocomial pneumonia is that agents that raise gastric pH promote the growth of bacteria in the stomach, particularly gram-negative bacilli that originate in the duodenum. Oesophageal reflux and aspiration of gastric contents along the endotracheal tube may then lead to colonization or pneumonia
• The clinical importance of the evidence that certain prophylactic agents may increase the incidence of nosocomial pneumonia is uncertain because many of the studies did not achieve statistical significance. However, the direction of the effect was the same in most of the studies.

Community acquired pneumonia

• A study population comprising 364 683 individuals, who developed 5551 first occurrences of pneumonia during follow-up[xi]. The incidence rates of pneumonia in non–acid-suppressive drug users and acid-suppressive drug users were 0.6 and 2.45 per 100 person-years. The increase in risk was most pronounced for PPIs and showed a clear dose-response relationship, which supports a real biological effect.

Therefore remembering to discontinue prophylaxis when the patient is no longer at high risk for stress ulceration can reduce the cost of stress ulcer prophylaxis. Such prophylaxis is unnecessary because the reduction in the rate of nosocomial gastrointestinal bleeding among non-critically ill patients is minuscule due to the low baseline risk. Despite this, several studies have demonstrated a high rate of ongoing stress ulcer prophylaxis among patients who are discharged from the ICU.

[i] Stress ulcer prophylaxis. Do critically ill patients need it?

[ii] The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients.

[iii] Prophylactic therapy for stress ulcer bleeding: a reappraisal

[iv] Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis.

[v] Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group.

[vi] ASHP Commission on Therapeutics. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis

[vii] Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group

[viii] Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis 

[ix] What risk factors contribute to C difficile diarrhea?

[x] Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses.

[xi] Risk of Community-Acquired Pneumonia and Use of Gastric Acid–Suppressive Drugs

Notes to go with Andy's VTE prophylaxis section:

DVT prophylaxis

Q1. Why do we employ VTE prophylaxis?

Pulmonary embolism remains the most common preventable cause of hospital death.

In the absence of appropriate prophylaxis, the incidence of DVT in hospital patients where objective diagnostic screening tests have been used to detect asymptomatic events has ranged from 10 to 80 percent in various medical and surgical groups.

So we need to be picking these patients.

Q2. Who should we be prescribing VTE prophylaxis to?

First we need to identify at risk patients. This is easier in critical care as that tends to include 100% of patients with common risks including - surgery or trauma, cancer, immobility, recent sepsis, presence of a central venous access device, inherited or acquired hypercoagulable states, age, significant medical co-morbidities.

For this reason it is easier to think why we shouldn’t prescribe it. Contraindications include – active bleeding, thrombocytopaenia, active ulcer, severe liver disease, or patients at risk of bleeds - ICH.

This is one of our common subset of patients- post neurosurgery. A systematic review and meta-analysis of randomized clinical trials evaluating VTE prophylaxis in patients undergoing elective cranial neurosurgery has estimated that for every 1000 patients who receive heparin prophylaxis, 91 VTE events will be prevented. Approximately 35 of these will be proximal DVT or PE, and only 9 to 18 will be symptomatic. On the other hand, 7 intracerebral hemorrhages and 28 more minor bleeds were estimated to occur if a heparin preparation is employed, versus none if a mechanical method of thromboprophylaxis is used.  

Q3. What do we use to prevent VTE?

We have two methods; drug or mechanical prophylaxis.

The slightly more contentious of the two is drugs. The most commonly used agents are LMWH and unfractionated heparins which are seemingly used interchangeably.

The most recent trial comparing the two in critically ill patients was the PROTECT trial; a randomised, multi centre study in 2011. They compared the LMWH dalteparin and unfractionated heparin with the outcome measure being patients with proximal leg DVTs. With almost 2000 patients in each arm there was no statistically significant difference between the two modalities. However, they did note that there was significantly less PEs with dalteparin, which called into question what we should be using as our main outcome measure for VTE. In terms of complications there was no difference between the two modalities in terms of bleeding and HIT.

So unfortunately neither is statistically preferable, but I think I would take dalteparin.

Why do we not use dalteparin? – might ask you – assuming cost, but not sure.

Q4. What about fondaparinux?

Fondaparinux is a newer agent chemically related to the low molecular weight heparins.

Fondaparinux has been evaluated in the prevention of VTE in patients undergoing orthopaedic surgery, general surgery, and in hospitalized medical patients. Fondaparinux 2.5 mg once/day by subcutaneous injection has been compared with the LMW heparin enoxaparin 40 mg once daily in patients undergoing total hip or total knee replacement, with enoxaparin 30 mg twice daily in patients undergoing total hip replacement, and with enoxaparin 40 mg daily in patients suffering hip fracture. A Meta-analysis of these four available trials concluded that the efficacy of fondaparinux was superior to that of enoxaparin.

Fondaparinux was shown to have efficacy equal to the LMW heparin dalteparin in patients undergoing high risk abdominal surgery, with a similar incidence of major bleeding [116]. In the subgroup of patients with cancer, fondaparinux therapy resulted in a significant decrease in the composite end point of asymptomatic or symptomatic DVT and non-fatal or fatal PE.

Another potential benefit of fondaparinux over LMWH or unfractionated heparin is that the risk for heparin-induced thrombocytopenia (HIT) is substantially lower. Furthermore, there have been case reports of fondaparinux being used to anticoagulate patients with established HIT as it has no affinity to platelet factor-4.

So it could definitely be a drug we start using more.

Q6. Mechanical methods seem fairly self explanatory, is there anything we should be thinking when applying mechanical prophylaxis?

We have two methods which are often applied together - graded compression stockings and intermittent pneumatic compression. These are very useful for the high risk of bleeding patient. Cochrane meta-analysis has concluded that the use of IPC alone was effective in the prevention of DVT in surgical patients (relative risk reduction 54 percent; 95% CI 42 to 63),

Must remember that it is contraindicated in patients with evidence of leg ischemia, peripheral vascular disease and recent skin grafts. There is also a hypothetical concern that patients who have been at bed rest or immobilized for a period of ?72 hours without any form of prophylaxis may be at risk of dislodging recently formed venous clots in the lower extremities following the use of IPC.

Conclude that it is very important in reducing morbidity and mortality. Should be reviewed daily especially in those patients considered contraindicated in case these factors have changed. We know the drugs are good, but no-one is yet unanimous on one. 

Some References:

• In the absence of appropriate prophylaxis, the incidence of DVT in hospital patients where objective diagnostic screening tests have been used to detect asymptomatic events has ranged from 10 to 80 percent in various medical and surgical groups.
• The PROTECT trial
• In a 2002 meta-analysis of four available trials, it was concluded that the efficacy of fondaparinux was superior to that of enoxaparin.
• A Cochrane meta-analysis has concluded that the use of IPC alone was effective in the prevention of DVT in surgical patients (relative risk reduction 54 percent; 95% CI 42 to 63)