In this episode I’ll:
1. Discuss an article about stress ulcer prophylaxis in the ICU.
2. Answer the drug information question “How long is the duration of chest wall rigidity from fentanyl?”
Article
Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU
Lead author: Mette Krag
Published in New England Journal of Medicine December 2018
Background
The is the publication of the SUP-ICU trial that we have been waiting for since it was discussed on episode 144. The authors sought to clearly outline the benefits and risks of prophylaxis for gastrointestinal stress ulceration with pantoprazole.
Methods
The trial took place across multiple European ICUs. Adults who were admitted to the ICU and judged to be at high risk of GI bleeding were randomly assigned to receive 40 mg of intravenous pantoprazole or placebo daily during the ICU stay. The primary outcome was death within 90 days after randomization.
Results
Over 3200 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (p=0.76). During the ICU stay, at least one clinically important event (defined as a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11).
In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group for a relative risk of 0.58. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days was similar in the two groups.
Conclusion
The authors concluded:
Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo.
Discussion
These results are similar to those obtained in a recent network meta-analysis, in which no significant differences were found in the rates of death or infectious complications between patients receiving placebo or no prophylaxis and those receiving proton-pump inhibitors. One important thing to balance is the risk of adverse events with potential benefits. There was no increase in the risk of pneumonia or c diff with the pantoprazole group in this study.
Although the reduction in GI bleeding did not translate to a reduction in mortality, it can still be considered a clinically relevant difference. Treating a GI bleed is costly and can use scarce resources such as blood products. Treating 58 patients with pantoprazole to prevent one GI bleed is very cost effective now that IV pantoprazole is generic and the chance of an adverse event is the same as placebo.
Pending the publication of clinical guidelines for stress ulcer prophylaxis, the inclusion criteria from this study can be reasonably used to determine which ICU patients need IV pantoprazole.
One or more of the following patient factors qualified for pantoprazole:
- Shock (continuous infusion with vasopressors or inotropes, systolic blood pressure < 90 mmHg, mean arterial blood pressure < 70 mmHg or lactate > 4 mmol/L)
- Acute or chronic intermittent or continuous renal replacement therapy
- Invasive mechanical ventilation which is expected to last > 24 hours
- Coagulopathy (platelets < 50 x 10^9/L or international normalized ratio (INR) > 1.5 or prothrombin time (PT) > 20 seconds) documented within the last 24 hours
- Ongoing treatment with anticoagulant drugs (prophylaxis doses excluded)
- History of coagulopathy (platelets < 50 x 10^9/L or INR > 1.5 or PT > 20 seconds) within 6 months prior to hospital admission
- History of chronic liver disease (portal hypertension, cirrhosis proven by biopsy, computed tomography (CT) scan or ultrasound, history of variceal bleeding or hepatic encephalopathy in the past medical history)
Drug information question
Q: How long is the duration of chest wall rigidity from fentanyl?
A:
We’ve all read the warning on fentanyl about how rapid infusion of high doses can lead to chest wall rigidity. This is a rare side effect of fentanyl that is largely eliminated by avoiding rapid infusion. What we know about how long it lasts comes mainly from a study in otherwise healthy volunteers. Of 12 healthy adult males who were given IV fentanyl at a rate of 150 micrograms/minute until a total of 15 micrograms/kg had been administered, half developed chest wall rigidity. When rigidity occurred, it started 3 +/- 0.9 (range 1-4) minutes after the peak plasma fentanyl concentration and lasted for 11.5 +/- 5.8 (range 7-23) minutes. Although none of these healthy volunteers required intubation, chest wall rigidity from fentanyl in critically ill patients has the potential to cause hypoxia and require intubation.
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Significantly fewer people in the control arm were coagulopathic – 300 vs 350 (table 1) which affect the result.