TITLE: 
Cisapride decreases gastric content aspiration in mechanically
		  ventilated patients



ABSTRACT.OBJECTIVE:
To determine the effect of the prokinetic agent cisapride in the
				prevention of aspiration of gastric contents.

ABSTRACT.DESIGN:
A prospective randomized two-period crossover study.

ABSTRACT.SETTING:
Fourteen-bed polyvalent intensive care unit in a University
				Hospital.

ABSTRACT.PATIENTS:
Eighteen intubated, mechanically ventilated patients who were
				seated in a semirecumbent position were studied.

ABSTRACT.METHOD:
Tc-99 m sulfur colloid (80 megabecquerels) was administered via
				nasogastric tube on 2 consecutive days. Patients randomly received cisapride
				(10 mg, via nasogastric tube) one day and a placebo the other. Bronchial
				secretions were obtained before and for 5 consecutive h after Tc-99 m
				administration. The radioactivity was measured in a standard amount (1ml) of
				bronchial fluid using a gamma counter and expressed as counts per min (cpm)
				after correction for decay.

ABSTRACT.RESULTS:
Sixteen out of 18 (88%) patients had increased radioactivity in
				bronchial secretions. The radioactivity increased over time both with and
				without cisapride, although it was lower in patients receiving cisapride than
				in those receiving a placebo. The cumulative bronchial secretion radioactivity
				obtained when patients received cisapride was significantly lower than when
				patients received a placebo: 7540 ± 5330 and 21965 ± 16080 cpm,
				respectively (P <0.05).

ABSTRACT.CONCLUSION:
Our results suggest that aspiration of gastric contents exists
				even in patients who are kept in a semirecumbent position. Moreover, cisapride
				decreases the amount of gastric contents aspiration in intubated and
				mechanically ventilated patients and may play a role in the prevention of
				ventilator associated pneumonia. Cisapride, even with the patient in the
				semirecumbent position, did not completely prevent gastric content
				aspiration.

BODY.INTRODUCTION:
The aspiration of gastric contents induces or exacerbates
		  bronchoconstriction and it is the most commonly recognized pathogenic factor
		  for the development of pneumonia, especially in ventilator-associated pneumonia
		  (VAP) [1,2].
The incidence of aspiration of gastric contents is high in intensive
		  care unit (ICU) patients and even higher in intubated and mechanically
		  ventilated patients. Gastrointestinal tract dysmotility is a relatively common
		  condition in critically ill patients and is associated with gastric contents
		  aspiration [3,4]. Additional risk
		  factors for gastric content aspiration included enteral feeding, naso or
		  oral-gastric tubes and position of the patients. Enteral feeding via a
		  nasogastric tube may also result in increased gastric volume, reflux and
		  Gram-negative bacterial overgrowth in the stomach [5].
		  Wide bore nasogastric tubes themselves probably impair the function of the
		  lower esophageal sphincter, thereby facilitating aspiration and bacterial
		  contamination of the tracheobronchial tree [6]. Moreover,
		  an important risk factor in causing the aspiration of gastric contents seems to
		  be the supine position. A semirecumbent position of mechanically ventilated
		  patients could help in part to prevent the aspiration of gastric contents into
		  airways, but aspiration still remains a problem [7].
		  Orozco-Levi and colleagues [8] showed a significant
		  increase in radioactivity count in oropharyn-geal contents after Tc99m isotope
		  instillation through nasogastric tube. This gastroesophageal reflux was
		  irrespective of body position. In contrast, the radioactivity count values in
		  bronchial secretions were higher in the supine position than in semirecumbency,
		  which suggests that the semirecumbent position helps prevent in part gastric
		  content aspiration. Apart from position, agents, such as erythromycin and
		  cisapride, increase the gastric motility and they could accelerate gastric
		  emptying and prevent gastric aspiration [9,10].
Cisapride is a very effective prokinetic agent that acts by increasing
		  the physiological release of acetylcholine from the postganglionic nerve
		  endings of the myenteric plexus without any associated dopamine antagonism
		  [10].
In this study, we assessed the effect of cisapride in the prevention
		  of pulmonary aspiration of gastric contents in mechanically ventilated patients
		  maintaining the benefit of a semirecumbent position.
Table 1Patient characteristics
No
Sex
Age
Diagnosis
APACHE II
Medications
MV
Outcome
1
F
58
SBH
22
Midazolam
5
S
2
M
54
ICH
20
—
5
D
3
M
54
COPD
28
Midazolam
5
D
4
F
70
COPD
30
Propofol
8
S
5
M
48
Head injury
24
Fentanyl, Midazolam
10
S
6
M
19
GBS
14
Fentanyl
5
S
7
M
40
Head injury
29
Fentanyl, Midazolam
6
D
8
M
67
Head injury
28
Fentanyl, Midazolam
7
S
9
M
76
ICH
28
Midazolam
6
D
10
M
41
Drug overdose
12
—
4
S
11
M
74
ICH
25
Midazolam, Fentanyl
4
D
12
M
74
Cardiac failure
27
Lorazepam
4
D
13
F
64
ICH
25
Midazolam
6
S
14
M
25
Head injury
17
Lorazepam, Fentanyl
5
S
15
M
26
Trauma
22
Fentanyl
5
S
16
M
55
Head injury
24
Propofol
8
S
17
M
62
ICH
27
—
6
S
19
M
35
Head injury
19
Propofol, Fentanyl
8
S
Mean

52

23

6

SD

17

5

1.7

M, male; F, female; S, survival; D, death; ICH, intracerebral
				hemorrhage; GBS, Guillain Barr syndrome; SBH, subarachnoid brain hemorrhage;
				COPD, chronic obstructive pulmonary disease; MV, days of mechanical
				ventilation.

BODY.MATERIALS AND METHODS:
BODY.PATIENTS:
Eighteen mechanically ventilated patients (15 men and three women,
			 mean age 52.33 ± 17.90 years) were included in this study. The protocol was
			 approved by the Medical Ethics Committee of The University Hospital of Ioannina
			 and consent was obtained from the patients' relatives. Patients with
			 gastrectomy, ileus, respiratory infections, sepsis and hemodynamic instability
			 (low blood pressure needing high doses of inotropes, or wide fluctuation of
			 blood pressure over time) were excluded from the study. The demographic data
			 and the underlying clinical conditions of these patients are summarized in
			 Table 1.

BODY.PROTOCOL:
All patients had a 5 mm diameter nasogastric tube in place for
			 enteral nutritional support and received sucralfate 2 g twice daily for stress
			 ulcer prophylaxis. The position of the nasogas-tric tube was radiographically
			 checked before the study. Sedation and all the other medications were kept
			 unchanged throughout the study (Table 1). Nobody was
			 given paralytic agents, antibiotics or inotropes. The enteral nutrition and
			 other medications via nasogastric tube were withheld 8 h before the onset and
			 during the study. The body position of the patients was semirecumbent at a 45
			 degree angle, and they were put in this position at least 8h before the
			 study.
All patients were intubated and mechanically ventilated with an
			 assist-control mode. A low level of positive end-expiratory pressure (PEEP) was
			 used (PEEP: 5 ± 1.7 cmH2O). The volume, pressure and the leaking
			 of the cuff of the endotracheal tube was checked, before and at the end of
			 every day of the study. The minimal volume and pressure necessary to prevent
			 air leaking around the cuff were used. The study lasted 2 consecutive days for
			 each patient. Eighteen hours before the study, the patients received, at 6 h
			 intervals, a cisapride suspension (Alimix, Janssen Pharmaceutica, Beerse,
			 Belgium; 1 mg/ml) in a dose of 10 mg, or a placebo given as a bolus randomly via
			 nasogastric tube. The next morning, 60 megabecquerels of Tc99m sulfur colloid
			 were carefully administered via the tube as described by Chernow and colleagues
			 [11]. Bronchial secretions were taken at zero time
			 (baseline radioactivity) and then once an hour for 5 consecutive h. The
			 secretions were taken in a sterile container by bronchial suction. The suction
			 catheter was placed at the level of the carina. The distance of the carina from
			 the tip of the endotracheal tube was measured on a chest X-ray. Just after the
			 end of this procedure, patients who had previously received cisapride were
			 given placebo and vice versa. On the second day, the procedure was repeated in
			 the same way. Blood samples were taken from the first five patients in the
			 study, before and 5 h after isotope instillation and checked for radioactivity.
			 Just before starting the procedure, bronchial secretion, oropharyngeal and
			 gastric samples were taken for microbiological cultures. A gentle suction of
			 gastric content was performed just before the administration of the
			 isotope.

BODY.MEASUREMENTS:
The activity of Tc99m was measured, using a gamma counter (Gamma
			 Counting system, Crystal TM II, 5400 Series, Packard Instrumental Company), in
			 a standard amount (1 ml) of bronchial secretions. The amount of radioactivity is
			 expressed as counts per min (cpm) after correction for decay according to the
			 equation of radioactive decay law:
N = N0.e-λt
where N0 is the number of parent nuclei present at t = 0,N
			 is the number remaining nuclei at time t, λ is a constant of
			 proportionality, called the decay constant, which is different for different
			 isotopes and e is the base of natural logarithm [12].
During the procedure, monitoring was performed with a two-lead
			 electrocardiogram (ECG) and a 12-lead ECG was performed before and soon after
			 the end of every procedure.

BODY.STATISTICS:
The differences between groups were tested for significance by
			 analysis of variance (ANOVA) test for repeated measures. Results are expressed
			 as mean± SD. A P value less than 0.05 was considered
			 significant.
Figure 1The radioactivity of bronchial secretions over time. The values at
				zero time represent the baseline radioactivity. Asterisk (*) denotes
				statistical significance between cisapride and placebo.
Figure 2The cumulative radioactivity of bronchial secretions with and
				without cisapride.


BODY.RESULTS:
Sixteen out of 18 patients (88%) demonstrated an increased
		  radioactivity in bronchial secretions and it increased over time both in
		  patients receiving cisapride or placebo. When patients received cisapride, the
		  radioactivity increased from 120 ± 18 cpm (baseline radioactivity at zero
		  time) to 1930 ± 1340 cpm at the fifth hour (P < 0.05). When
		  patients received a placebo the radioactivity increased from 115 ± 22 cpm
		  (baseline radioactivity at the zero time) to 6825 ± 5100 cpm 5 h later
		  (P < 0.01). There was no significant difference in baseline
		  radioactivity of bronchial secretions whether the patients were given
		  cisa-pride or placebo. The change in radioactivity of bronchial secretions over
		  time is demonstrated in Fig 1. The difference in
		  radioactivity during cisapride and placebo administration became statistically
		  significant after the third hour (P < 0.05). The cumulative
		  bronchial secretion radioactivity obtained when patients received cisapride was
		  significantly lower than when patients received a placebo (7540 ± 5330 and
		  21965 ± 16080cpm, respectively; P < 0.05; Fig 2).
The microbiological cultures showed that 10 patients had identical
		  microorganisms colonizing the stomach, oropharyngeal area and bronchus. Five
		  patients had the same microorganisms only in the oropharyngeal content and
		  bronchial secretion, and different ones in the gastric content. Three patients
		  had different microorganisms in stomach, oropharynx and bronchus. Two of the
		  studied patients developed VAP during their stay in ICU; both patients had the
		  stomach, oropharynx and bronchus colonized with the causative bacteria of VAP,
		  which were detected by quantitative cultures of protected brush specimens.
There was no significant difference in cuff pressure between
		  measurements before and at the end of the study.
There was no difference in the blood radioactivity before and 5 h after
		  isotope administration, as it was the same as the background radioactivity.
No side effects of cisapride were observed during this study. No
		  cardiac arrhythmia or QT interval prolongation was noted.

BODY.DISCUSSION:
This study demonstrates that cisapride significantly reduced the
		  pulmonary aspiration of gastric contents in mechanically ventilated patients
		  although the conventional protective methods, such as semirecumbent position
		  and regular checking of cuff leaking, even with cisapride administration are
		  not sufficient to prevent gastric content aspiration completely.
In critically ill patients receiving mechanical ventilation
		  gastrointestinal motility is often impaired [3,4]. The precise mechanism leading to this gastroparesis is
		  still unknown. Medications such as opiates and dopamine [13,14], hyperglycemia [15] or increased intracranial pressure [16] have all been shown to depress the antral motor activity
		  in experimental or clinical conditions. This situation favors not only
		  gastroesophageal reflux but also duo-denogastric reflux, thereby promoting the
		  colonization of the stomach with gastric Gram negative pathogens [17,18]. Enteral nutrition in patients
		  with inadequate gastric emptying can increase the risk of aspiration, and
		  expand the size of the gastric bacterial reservoir by increasing the gastric
		  volume and the pH. Today most investigators agree that gastric colonization
		  with potentially pathogenic microorganisms is important in the pathogenesis of
		  VAP [17,19,20]. Moreover, nasogastric tubes themselves probably impair
		  the function of the lower esophageal sphincter thereby promoting aspiration. In
		  addition, the supine position of patients promotes aspiration and the
		  semirecum-bent position helps minimize the aspiration of gastric contents to
		  lower airways [7,8].
Our results showed that aspiration in mechanically ventilated patients
		  occurs even when they are kept in a semire-cumbent position. The administration
		  of cisapride significantly decreases aspiration in these patients. A properly
		  inflated cuff was insufficient to prevent aspiration to lower airways. The
		  incidence of gastric content aspiration in our group of patients was very high.
		  One explanation could be the high percentage of neurological diseases, which
		  are included in our patient population, because severe head injury has been
		  associated with impaired gastric emptying [16]. Another
		  cause of the high incidence of aspiration could be the sedation received by the
		  majority of the patients. There is no clear explanation for the absence of
		  gastric content aspiration in two patients. It is noteworthy, though, that one
		  of them did not receive sedation and the other was given low-dose (5mg/h)
		  mida-zolam. Both survived, and their age, APACHE II score and the days of
		  mechanical ventilation at the day of the study were equivalent to those of the
		  other patients.
These findings are in agreement with other investigators who found
		  that cisapride prevents the morphine-induced delay in gastric emptying [21]. It also significantly accelerates gastric emptying both
		  in patients with gastroesophageal reflux disease and in patients with delayed
		  gastric emptying caused by idiopathic or postsurgical reasons [22]. It has also been suggested that cisapride can minimize
		  the risk of aspiration pneumonia in patients with long-term enteral feeding
		  [23]. In critically ill patients with gastric dilatation
		  and functional gastric paralysis the administration of cisapride showed a
		  clinical benefit [24,25].
		  Moreover, cisapride increases the lower esophageal sphincter pressure in normal
		  volunteers and in patients with reflux disease [26]. The
		  velocity of transit in the esophagus remains unchanged with cisapride, but an
		  increase in distal peristalsis is noted [27].
Oral cisapride usually has few side effects. Nevertheless, cardiac
		  arrhythmias, especially torsade de pointes, and prolonged QT intervals with a
		  potentially fatal outcome have been described in patients with concomitant use
		  of medication that is metabolized by the cytochrome P-450 3a4 isoenzyme, eg
		  imidazole antibiotics or macrolides [28]. Cisapride
		  should be administered with caution in patients who are on any medication known
		  to prolong QT interval and in those with renal insufficiency, a history of
		  arrhythmia or cardiac disease. None of our patients received any of the above
		  medications and, possibly for this reason, no side effects were noted during
		  the period of cisapride administration.

BODY.CONCLUSION:
In summary, our results suggest that cisapride decreases the risk of
		  aspiration of gastric contents in intubated and mechanically ventilated
		  patients who are kept in a semirecumbent position. Conventional protective
		  methods though, such as the semirecumbent position and regular checking of cuff
		  leaking, even with cisapride administration are not sufficient to prevent
		  gastric content aspiration completely. Further studies are needed to establish
		  if this drug helps in the prevention of ventilator associated pneumonia,
		  bronchitis or bronchoconstriction.

Question: Compared to placebo what was the result of cisapride (10 mg, via nasogastric tube) on The cumulative bronchial secretion radioactivity?
Evidence: The cumulative bronchial secretion radioactivity
				obtained when patients received cisapride was significantly lower than when
				patients received a placebo: 7540 ± 5330 and 21965 ± 16080 cpm,
				respectivel
Answer: significantly decreased