Cooling Dogs

Motivation: Lately, hypothermia has not been good enough for me.  There have been too many people who have suffered cardiac arrests at home and ended up severely impaired despite receiving mild hypothermia according to protocol.  Can we do better?  For instance, if we can quickly institute deep hypothermia, is it any better?

Some of the coldest studies in this field have been performed in dogs.  In this amazing study, dogs were tested for neurological recovery after many hours of hypothermia.

Paper: Nozari A, Safar P, Wu X, et. al. "Suspended Animation Can Allow Survival without Brain Damage after Traumatic Exsanguination Cardiac Arrest of 60 Minutes in Dogs." J Trauma (2004); 57: 1266-1275.

Methods: Fourteen dogs were sedated with ketamine and halothane and supported with positive pressure ventilation.  The dogs were then exsanguinated over fiver minutes to cardiac arrest.  At two minutes, flush of saline at 2 degrees Celsius was administered in femoral artery to achieve tympanic temperature of 10 degrees Celsius.  In 6 dogs, reperfusion was performed after 60 minutes of cardiac arrest.  In 8 dogs, to simulate trauma, splenic injury was inflicted prior to cardiac arrest.  During arrest time of 60 minutes, the spleen was transected.  Outcome was determined by overall performance category (1 to 6 with 1 being normal and 6 being death) at 72 hours.

Results:
Resuscitation: All fourteen dogs were successfully resuscitated from cardiac arrest.

Control group: All six dogs in the control group were neurologically normal after 72 hours (they were judged to be identical in behavior to their pre-intervention condition).

Trauma group: Of the eight dogs who underwent splenectomy during the cardiac arrest time, four were normal after resuscitation.  One had moderate disability while another dog had severe disability.  Two dogs remained in coma.

Discussion: In this remarkable study, dogs could be maintained in suspended animation at 10 degrees Celsius when rapidly cooled after two minutes.  The most obvious problem in extending this strategy to the real world is that Emergency Medical response time is certainly greater than two minutes.  However, while we know that delayed cooling leads to increased brain injury, trials using suspended animation have not been tried in human beings even in settings in which prompt response is possible (such as hypothermia instituted in the field).  One of the other interesting findings in the study is that operative trauma during suspended animation (splenectomy) leads to a worse outcome after reperfusion.  The cause is unclear in this case but could be secondary to need for increased recovery times (all dogs were timed at 72 hours and not at best long term performance) or possibly injury from increased systemic inflammation.

Proton pump inhibitors in liver cirrhosis

Motivation: A patient with known liver cirrhosis is admitted. His home medication list includes a proton pump inhibitor (PPI). If there is no other indication (such as peptic ulcer disease), what is the evidence for use of PPIs in liver cirrhosis - in particular, are PPIs effective in preventing GI bleed in liver cirrhosis? Are there any risks associated with PPI use?

Literature:
1) LEVEL OF EVIDENCE: retrospective study
 Garcia-Saenz-de-Sicilia M et al. PPIs are not associated with a lower incidence of portal-hypertension-related bleeding in cirrhosis. World J Gastroenterol. 2010 16(46):5869-73.

This was a restrospective study that included 105 patients with cirrhosis with endoscopy-proven portal hypertension. Patients were divided into 2 groups: those who used PPIs (45.5%) and those who did not. Seventeen (16.1%) patients had upper GI bleeding, due to either esophageal varices or portal HTN gastropathy. Of these 17 patients 9 used PPIs, while 8 did not use PPIs (p=0.51). Thus, in this retrospective study, use of PPIs was not associated with development of GI bleed related to portal HTN.

2) LEVEL OF EVIDENCE: literature review

Siple JF et al. Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites. Ann Pharmacother. 2012 46(10):1413-8.

This was a literature review that evaluated the use of PPIs in cirrhosis and ascites, ultimately including 1 case study, 8 restrospective case-controlled studies, 1 meta-analysis. Authors summarize that there is a possible risk of association between use of PPIs and increased risk of SBP and C diff infection in cirrhosis/ascites. However, they note that this association has yet to be established by prospective trials.

3) LEVEL OF EVIDENCE: RCT 

Shaheen NJ et al. Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial. Hepatology. 2005; 41(3):588-94

In this study, the use of PPI after elective esophageal variceal ligation (EVL) was investigated. This study was designed as a double-blinded, placebo-controlled RCT where 44 subjects (42 completed the study) who underwent EVL were randomized to the pantoprazole arm (pantoprazole 40 mg IV after EVL x 1 then pantoprazole 40 mg PO x 9 days) or the placebo arm (placebo IV x1 after EVL then placbo PO x 9 days). Upper GI scope 10-14 days after the EVL procedure showed that while both groups had the same mean number of ulcers, ulcers in the pantoprazole arm had smaller average size (p < 0.01). 

Thoughts: I was unable in my initial literature search here to find definitive evidence that PPIs should be used for primary prevention for GI bleeding secondary to portal hypertension in liver cirrhosis. One retrospective study by Garcia-Saenz-de-Sicilia et al. (2010) did not show differences between patients who took PPIs and those who did not, but this was a relatively small sample that was studied retropectively. The RCT by Shaheen et al. (2005) provide evidence for using pantoprazole directly after EVL, though it was a short, limited course of PPI use that was studied. Authors Siple et al. (2012) recently draw from existing literature to caution on the potential risk of infection (SBP, C diff) when using PPIs, though there is no prospective, RCT evidence for this concern. It is important to think about the indications of using PPIs in patients, realizing that there lacks evidence for use of PPIs in primary prevention of GI bleeds related to portal HTN in liver cirrhosis (Garcia Saenz-de-Sicilia et al., 2010). While one should be aware of possible adverse effects like increased risk of infection (Siple et al., 2012), there also does not exist evidence against using PPIs in liver cirrhosis if there is a reasonable primary indication for PPI use (e.g. peptic ulcer disease).