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Authors and Disclosures


Arnaud Gacouin, MD, Christophe Camus, MD, Antoine Gros, MD, Sonia Isslame,
MD, Sophie Marque, MD, Sylvain Lavoué, MD, Loic Chimot, MD, Pierre-Yves
Donnio, PhD, and Yves Le Tulzo, MD

Service de Maladies Infectieuses et Réanimation Médicale (AG, CC, AG, SI, SM, SL,
LC, YLT) and the Laboratoire de bactériologie (P-YD), Hôpital Pontchaillou, Rennes,
France.

From Critical Care Medicine

Constipation in Long-term Ventilated


Patients: Associated Factors and
Impact on Intensive Care Unit
Outcomes
Arnaud Gacouin, MD; Christophe Camus, MD; Antoine Gros, MD; Sonia Isslame, MD;
Sophie Marque, MD; Sylvain Lavoué, MD; Loic Chimot, MD; Pierre-Yves Donnio,
PhD; Yves Le Tulzo, MD

Posted: 10/12/2010; Crit Care Med. 2010;38(10):1933-1938. © 2010 Lippincott Williams


& Wilkins

Abstract and Introduction

Abstract

Objectives: To characterize the factors associated with delayed defecation in long-term


ventilated patients and to examine the relationship between delayed defecation and
logistic organ dysfunction scores, acquired bacterial infections, and mortality in the
intensive care unit.
Design: Prospective observational cohort study.
Setting: A 21-bed polyvalent intensive care unit in a university hospital.
Patients: A total of 609 adult patients admitted over a 41-month period who underwent
mechanical ventilation for ≥6 days.
Interventions: None.
Measurements and Main Results: Three hundred fifty-three patients (58%) passed
stools ≥6 days after they were admitted to the intensive care unit ("late" defecation).
Patients with early and late defecation had similar general characteristics when admitted
to the intensive care unit and had similar logistic organ dysfunction scores on the first day
of mechanical ventilation. Several variables were independently associated with a delay
in defecation: a Pao2/Fio2 ratio of less than 150 mm Hg (adjusted hazard ratio 1.40; 95%
confidence interval: 1.06–1.60; p = .0073), a systolic blood pressure between 70 and 89
mm Hg (adjusted hazard ratio 1.48; 95% confidence interval: 1.17–1.79; p = .002), and
systolic blood pressure <68 mm Hg (adjusted hazard ratio 1.29; 95% confidence interval:
1.01–1.60; p = .03). Logistic organ dysfunction scores were significantly higher on the
fourth and ninth days of mechanical ventilation in patients with late defecation than in
those with early defecation. The crude intensive care unit mortality rate was 18% in
patients with early defecation and 30% in patients with late defecation (p < .001).
Acquired bacterial infections at any site occurred in 34% of patients with early defecation
and 66% of patients with late defecation (p < .001).
Conclusion: A Pao2/Fio2 ratio of <150 mm Hg and systolic blood pressure of <90 mm
Hg during the first 5 days of mechanical ventilation were independently associated with a
delay in defecation. Our results suggest that constipation is associated with adverse
outcomes in long-term ventilated patients.

Introduction

Many gastrointestinal complications have been described in patients receiving


mechanical ventilation (MV); these include erosive esophagitis, stress-related mucosal
damage, high gastric residuals, diarrhea, and constipation.[1] Constipation is probably the
gastrointestinal complication that has received the least amount of attention in patients
receiving long-term MV. Recent studies have shown that constipation is still a frequent
problem[2, 3] in critically ill patients. The critically ill patients may become constipated for
several reasons, including immobility, hypotension, treatment with vasopressors or
morphinics, or lack to access to appropriate facilities.[1–3] Constipation has been
associated with difficulties in weaning from MV,[3] prolonged length of stay and
increased intensive care unit (ICU) mortality.[4, 5] There is a lack of data regarding
constipation in ventilated patients. Much of our understanding of the interactions between
MV and dysmotility of the lower digestive tract relies on experimental studies.[1] In
addition, the impact of delayed defecation in long-term ventilated patients is largely
unknown.

This study sought to characterize the causes of delayed defecation in critically ill patients
receiving MV. We also compared length of ICU stay, mortality rate in the ICU, duration
of MV and a central venous catheter, and the proportion of patients with bacterial-
acquired infections according to whether patients had delayed defecation. We performed
a prospective observational study on a large cohort of long-term ventilated patients.

Materials and Methods


Study Design

A prospective observational cohort study was performed in our ICU between March 1,
2005, and December 31, 2008. This ICU is a mixed 21-bed ICU that admits mostly
medical patients in a 1950-bed teaching hospital. The study was approved by the
hospital's Institutional Review Board; because of the noninterventional nature of the
study, informed consent was not required.

Patients

Patients who had been on MV for ≥6 days were eligible for the study; patients were
included if they were ≥18 yrs of age, were placed on MV <24 hrs before or 48 hrs after
admission to the ICU, and if they did not have treatment withdrawn during the first 6
days of MV. Pregnant patients, readmitted patients, and those admitted immediately after
gastrointestinal surgery were excluded from the study. Patients were followed for the
passage of stools and for ICU-acquired bacterial infections until they were discharged
from the ICU, until the decision for palliative treatment was made, or until death. During
the recruitment period, the feeding policy in our ICU did not change and consisted of
starting enteral nutrition as soon as possible through a nasogastric tube with a peristaltic
pump. The feeding policy goal was 25–30 kcal·kg−1·day−1. The decision to stop the diet
was at the discretion of physicians based on the recovery of gastric residues and findings
from the daily abdominal examination. The management of constipation was not
protocolized. Most often, patients were first given a little enema with sorbitol to obtain
the relief of constipation followed by treatment with lactulose if no stools were passed.
The use of prokinetic agents was exceptional during the first 6 days of MV.

Our ICU followed written policies for hygiene measures and isolation precautions; these
policies complied with the recommendations of the US Centers for Disease Control and
Prevention and the French National Technical Committee for Nosocomial Infections. On
June 1, 2007, our policy for the prevention of acquired infections changed. In addition to
our standard care protocol to prevent acquired infections, especially ventilator-associated
pneumonia, all intubated patients who were likely to receive MV for >48 hrs received a
combination of two decontamination regimens similar to the one assessed by our group in
a previous study.[6] The combined decontamination regimen included selective
decontamination of the digestive tract (i.e., the use of a solution containing polymyxin E,
tobramycin, and amphotericin B applied to the oropharyngeal cavity and administered
through the nasogastric tube every 6 hrs) with a regimen against Staphyloccocus aureus
(i.e., washing of the body every 12 hrs with a 4% solution of chlorhexidine plus the
application of mupirocin calcium 2% into both anterior nares every 8 hrs from day 0 to
day 4 of MV).

Data Collection

Age, sex, Simplified Acute Physiologic Score II, and admission type (medical,
emergency, or elective surgery) were recorded at admission to the ICU. The reason for
MV (acute respiratory failure, exacerbation of chronic obstructive pulmonary disease,
neurologic problem, postoperative, or miscellaneous) and the time elapsed between
intubation and the initiation of enteral nutrition were also recorded. Logistic organ
dysfunction (LOD) scores[7] were calculated on the first, fifth, and, when available, tenth
days of MV. In this population of patients who underwent MV for ≥6 days, we believed it
relevant to collect data during the first 5 days of MV and then to follow patients for the
ICU outcomes. Between day 0 and day 4 of MV, the following variables were recorded
daily: the highest level of positive end expiratory pressure (PEEP) used the lowest
Pao2/Fio2 ratio, and the lowest systolic blood pressure (SBP) value. For each of these
three variables, patients were classified based on the cutoff values used in the LOD
system for severity scoring. Only two categories were considered for the Pao2/Fio2 ratio:
<150 mm Hg and ≥150 mm Hg. Similarly, three categories were identified for the lowest
SBP: <69 mm Hg, between 70 and 89 mm Hg, and ≥90 mm Hg. In addition, the highest
level of PEEP applied during the first 5 days of MV was arbitrarily categorized as ≤5 cm
H2O, 6–10 cm H2O, and >10 cm H20. We recorded treatment with lactulose[4] and
morphine[1, 3, 5] within the first 5 days of MV and treatment with epinephrine or
norepinephrine[1, 5] if it was administered for more than 24 hrs. Dopamine was not used in
our ICU. Gastric residuals were collected daily until the fifth day of MV. Regarding ICU
outcomes, in addition to mortality, we recorded the duration of MV, the use of central
venous catheter, the length of the ICU stay, and the proportion of patients with ICU-
acquired bacterial infections. The production of stools was assessed by nurses who
routinely use a semiquantitative tool for scoring (i.e., "none," "normal × number by day,"
and "watery × number by day").

Definitions

Based on previous studies published by van der Spoel et al,[5] "early" passage of normal
or watery stools occurred within 6 days of ICU admission; "late" defecation occurred ≥6
days after ICU admission. The methods used to record bacterial infections for the purpose
of this study have been reported elsewhere.[6] The diagnosis of ventilator-associated
pneumonia required that bronchoalveolar lavage results demonstrated 104 or more
colony-forming units/mL.[8, 9] Two groups of patients were considered in the analysis:
patients with early defecation and patients with late defecation.

Study End Points

The primary end point was to use univariate and multivariate analysis to identify the
variables associated with time until the first defecation. Variables studied were Simplified
Acute Physiologic Score II on admission to the ICU, LOD scores on day 0 of MV, and
SBP, vasopressor use, Pao2/Fio2 ratio, applied PEEP level, and morphinics use during the
first 5 days of MV.

The secondary end points included the comparison of length of ICU stay, ICU mortality,
proportions of ICU-acquired bacterial infections, LOD scores, and signs of intolerance to
enteral feeding[2, 10, 11] between patients with early defecation and those with late
defecation. The use of decontamination regimens was considered as a confounding
variable in the assessment of acquired bacterial infections.
Statistical Analysis

Continuous variables were expressed as medians with an interquartile range and were
compared with nonparametric tests (e.g., the Mann-Whitney U test). Proportions were
compared with a chi-square test or Fisher's exact test when required. Tests were two-
sided and p < .05 was considered to be significant. A univariate analysis and a
multivariate analysis using Cox regression model with a stepwise selection procedure
were performed to identify variables associated with the time until defecation. Variables
with p value <.10 in univariate analysis were entered in the final model. Risk was
expressed by a hazard ratio. An analysis of variance was used to compare repeated
measures of gastric residuals.

Results

Patients

During the 41 months of the study, 3712 patients were admitted to the ICU, 874
underwent MV for ≥6 days, and 609 were included in the study. Patients who were not
included into the study were mainly those who had been intubated for >24 hrs before they
were admitted to the ICU (Fig. 1). Among the 609 patients in the study, 256 (42%) had
"early" passage of stools and 353 (58%) had "late" passage of stools. Patients with early
passage of stools and patients with late passage of stools did not differ significantly in
their baseline characteristics (Table 1). Enteral feeding was started within 2 days of the
onset of MV in 160 patients (62%) who experienced the early passage of stools and in
203 patients (57%) who experienced the late passage of stools (p = .22). Twenty-six
patients (10%) with the early passage of stools and 13% of patients with the late passage
of stools were fed exclusively parenterally during the first 5 days of MV (p = .30). The
first stool was watery in 84 patients (33%) with early passage of stools and in 52 patients
(15%) with late passage of stools (p < .001). From day 0 to day 4 of MV, few patients
received lactulose (eight patients [3%] who had early passage of stools and 17 patients
[5%] who had late passage of stools, p = .30). Lactulose was administered mostly in
cirrhotic patients for the treatment of hepatic encephalopathy. Two patients received
erythromycin and one patient received neostigmine during the first 5 days of MV.

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Table 1. Patients characteristics

All Patients With Early Patients With Late


Patients Passage of Stools a Passage of Stools
No. of patients 609 256 353
61 (50–
Age, median yrs (IQR) 60 (50–71) 61 (49–73)
73)
SAPS II, median points (IQR) 50 (39– 49.5 (36–64) 50 (40–62)
63)
Male, n (%) 388 (64) 155 (61) 233 (66)
Admission type, no. (%)
Medical 484 (79) 212 (83) 272 (77)
Emergency surgery 95 (16) 31 (12) 64 (18)
Elective surgery 30 (5) 13 (5) 17 (5)
Reason for MV, no. (%)
Acute respiratory failure 218 (36) 91 (36) 127 (36)
Exacerbation of COPD 69 (11) 34 (13) 35 (10)
Neurologic 119 (20) 47 (18) 72 (20)
Postoperative 26 (4) 11 (4) 15 (4)
Miscellaneous 117 (29) 73 (28) 104 (30)
Time of enteral nutrition
2 (1–4) 2 (1–3) 2 (1–4)
initiation, b median days (IQR)
Treatment with combined
decontamination regimen, c no. 249 (41) 113 (44) 136 (39)
(%)

IQR, interquartile range; SAPS, Simplified Acute Physiologic Score; MV, mechanical
ventilation; COPD, chronic obstructive pulmonary disease.
a
Passage of stools before §6 days after intensive care unit admission; b from the time of
intubation; c selective decontamination of the digestive tract and nasal mupirocin with
chlorhexidine body washing. Any significant difference was found when patients with
early passage of stools were compared with those with late passage of stools for the
variables listed in the table.
Figure 1. Flow chart of patients. ICU, intensive care unit.

Variables Affecting the Time to First Defecation


For the entire study population, the median time until the first passage of stools was 6
days. Table 2 shows the results of univariate and multivariate analysis for the variables
affecting time until the first passage of stools. A Pao2/Fio2 ratio of <150 mm Hg (adjusted
hazard ratio 1.40; 95% confidence interval: 1.06–1.60; p = .0073), SBP between 70 and
89 mm Hg (adjusted hazard ratio 1.48; 95% confidence interval: 1.17–1.79; p = .002),
and SBP <69 mm Hg (adjusted hazard ratio 1.29; 95% confidence interval: 1.01–1.60; p
= .03) were independently associated with a delay in defecation.

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Table 2. Unadjusted and adjusted hazard ratios for time of first passage of stools
from intensive care unit admission

Unadjusted Hazard Ratio (95% CI)


Variables p p
Ratio (95% CI) Adjusted Hazard
Simplified Acute Physiologic
1.003 (0.998–1.008) .30
Score II, points
Logistic organ dysfunction
1.015 (0.988–1.043) .27
score at day 0 of MV, points
Treatment with morphinics,
1.37 (1.03–1.82) .03 1.18 (0.88–1.59)
yes
Treatment with epinephrine or
1.32 (1.09–1.59) .003 1.08 (0.88–1.34) .44
norepinephrine, yes
Highest level of PEEP applied a
>10 cm H2O, yes (reference
1 1
group)
Between 6 and 10 cm H20,
.76 (0.57–0.99) .05 0.78 (0.59–1.03) .10
yes
≤5 cm H2O, yes .65 (0.49–0.84) .0014 0.79 (0.59–1.06) .12
PaO2/FIO2 ratio <150 mm Hg, a
1.44 (1.20–1.72) <.0001 1.40 (1.06–1.60) .003
yes
Lowest systolic blood pressure recorded a
≥90 mm Hg, yes (reference
1 1
group)
Between 70 and 89 mm Hg,
1.53 (1.24–1.88) <.0001 1.48 (1.17–1.79) .002
yes
≤69 mm Hg, yes 1.39 (1.10–1.75) .006 1.29 (1.01–1.60) .03
CI, confidence interval; MV, mechanical ventilation; PEEP, positive end expiratory
pressure.
a
Recorded from day 0 to day 6 of mechanical ventilation.

Secondary End Points

Length of ICU stay, the duration of MV and central venous catheter use, and mortality
rates were significantly greater in patients with late defecation than in patients with early
defecation (Table 3). The proportion of patients with an ICU-acquired bacterial infection
at any site was significantly lower in the group of patients with early defecation than in
the group of patients with late defecation (34% vs. 66%, respectively; p <.01). During the
last 18 months of the study, 249 patients (41%) received the combination of two
decontamination regimens in addition to our standard protocol for the prevention of ICU-
acquired bacterial infections; these patients included 113 (44%) of the 256 patients who
experienced the early passage of stools and 136 (39%) of the 353 patients who
experienced the late passage of stools (p = .16). In both the early and late defecation
groups, the proportion of patients with acquired bacterial infections at any site was
significantly lower in those who received the combined decontamination regimens than
in those who did not. We observed similar findings for bacterial ventilator-associated
pneumonia.

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Table 3. Comparisons of the secondary objectives whether that the passage of stools
was early or not a

Patients With Early Passage Patients With Late Passage of


of Stools b Stools
No. of patients 256 353
Death in the ICU, no. (%) 47 (18) 107 (30) c
Length of ICU stay,
15 (11–24) 17 (12–30) d
median days (IQR)
Duration of CVC, median
10 (5–14) 12 (7–19) d
days (IQR)
Duration of MV, median
11 (8–17) 14 (9–24) d
days (IQR)
Bacterial infection at any
77 (34) 150 (66) d
site, no. (%)
VAP before day 6 of MV,
24 (9) 29 (8)
no. (%)
VAP from day 7 of MV,
38 (15) 114 (33) d
no. (%)
Combined Decontamination Combined Decontamination
Regimens Regimens
Yes No Yes No
No. of patients 113 143 136 207
Bacterial infection at any
24 (21) 53 (37)e 37 (27) 117 (55) e
site, no. (%)
VAP before day 6 of MV,
6 (5) 18 (13) e 6 (4) 23 (11) e
no. (%)
VAP from day 7 of MV,
12 (8) 26 (18) f 28 (20) 86 (41) e
no. (%)

ICU, intensive care unit; IQR, interquartile range; CVC, central venous catheter; MV,
mechanical ventilation; VAP, ventilator-associated pneumonia.
a
For ICU-acquired bacterial infections, patients were compared also whether that the two
decon-tamination regimens (i.e., selective decontamination of the digestive tract and
nasal mupirocin with chlorhexidine body washing) were received or not; b passage of
stools <6 days after ICU admission; c early vs. late passage of stools, p < .05; d early vs.
late passage of stools, p < .01; e combined vs. no combined decontamination regimen, p
< .05; f combined vs. no combined decontamination regimen, p = .05.

The LOD scores calculated for patients who experienced the early passage of stools and
those who experienced the late passage of stools did not differ significantly on day 0 of
MV; however, they were significantly lower on day 4 of MV and when available on day
9 of MV for patients who passed stools early (Fig. 2).
Figure 2. Logistic organ dysfunction scores in patients who produce stools within 6 days
of intensive care unit admission (early passage of stools) compared at day 0, day 4, and
day 9 of mechanical ventilation (MV) with those calculated in patients who produced
stools later (late passage of stools). Data are presented as a box and whisker plot showing
median, 25th percentile, and 75th percentile with the whiskers demonstrating the range.

Similar proportions of patients presented vomiting between day 0 and day 6 of MV (29
patients [11%] with early defecation and 56 patients [16%] with late defecation; p = .11).
Daily gastric residual volumes recovered during this period did not differ significantly
between patients with early or late defecation (p = .33 by analysis of variance for
repeated measures; Fig. 3).

Figure 3. Means and 95% confidence intervals of daily gastric residuals volumes
recovered during the first 5 days of mechanical ventilation in patients with early and in
those with late passage of stools. ANOVA, analysis of variance.
Discussion

In this large population of patients with prolonged MV, near 60% experienced delayed
defecation. In accordance with experimental data,[1, 12–14] the results of a univariate
analysis suggest that in addition to the use of opiates and vasopressors, levels of PEEP
applied, the severity of hypotension, and the severity of hypoxemia may have a
significant impact on the production of stools in ventilated patients. A Pao2/Fio2 ratio of
<150 mm Hg and SBP values of <90 mm Hg during the first 5 days of MV were
significantly associated with a delay in defecation. Higher LOD scores and a greater ICU
mortality rate show that when patients did not pass stools by the fourth day of MV, the
severity of illness on day 4 and day 9 of MV was greater. The proportion of patients with
bacterial ICU-acquired infections at any site was significantly lower in the patients who
passed stools "early" compared with those who passed stools later. Furthermore, the
efficacy of selective decontamination of the digestive tract in association with nasal
mupirocin and chlorhexidine body washing to prevent acquired bacterial infections did
not appear to be reduced by delayed defecation. Manifestations of upper digestive
intolerance were not more frequent in patients with delayed defecation than in those with
early defecation.

Previous researchers have asked whether late defecation is a symptom of organ failure or
the effect of vasopressors.[5] In the present study, hypotension (SBP of <90 mm Hg) was
independently associated with delayed defecation but not with treatment with
vasopressors. Similarly, hypoxemia (a Pao2/Fio2 ratio of <150 mm Hg) seemed to have a
more significant impact on the time before the production of stools than the levels of
PEEP applied. These results support the hypothesis that delayed defecation is more
related to the severity of hypoxemia and hypotension than to the treatments used for these
organ dysfunctions. In addition, our results suggest that a delay in defecation was not
related to a greater disease severity at the initiation of MV; Simplified Acute Physiologic
Score II and LOD scores on day 0 did not differ significantly between the "early" or
"late" defecation groups. LOD scores were higher on day 4 and day 9 of MV in patients
with late defecation. We are aware that a Pao2/Fio2 ratio <150 mm Hg and a SBP <90 mm
Hg during the first 5 days of MV were associated with delayed defecation, that both are
items in the LOD score, and that some association of Pao2/Fio2 ratios and SBP is to be
expected.

Experimental studies show that altered lower gut motility is one of the consequences of
splanchnic hypoperfusion and consequent gut hypoxia.[1, 14] Decreased cardiac output
secondary to reduced preload, hypotension, impaired venoconstriction with the use of
opiates, and increased vascular resistance can all be involved in a decrease in splanchnic
blood flow in patients undergoing MV; this is especially true in hypovolemic patients. A
randomized, placebo-controlled study by van der Spoel et al[4] showed that both lactulose
and polyethylene glycol were more effective than a placebo in promoting defecation in
ventilated patients. Nevertheless, the use of laxatives exposes patients to the risk of
diarrhea. Research is needed to investigate whether rigorous management of opiates,
treatment of hypoxemia through the avoidance of high levels of PEEP, and emphasis on
the correction of hypovolemia rather than the use of vasopressors to treat hypotension
influence the course of constipation.

Like previous researchers,[2–5] we found that ICU morbidity and mortality were higher in
patients with late defecation. Several investigators have suggested a role for gut failure
and altered gut barrier function in the pathogenesis of multiple organ dysfunction
syndrome. Although not demonstrated here, constipation itself could affect the severity of
disease in ICU patients. Constipation is a risk factor for intra-abdominal hypertension and
this hypertension may cause subsequent organ dysfunction.[15–17]

Acquired bacterial infections were significantly more common in patients with late
defecation; this finding has not been previously reported and could be explained in part
by the longer exposure to MV and central venous catheter. Other researchers have
suggested that stasis of feces could reduce the efficacy of selective decontamination of
the digestive tract.[5, 18] Our results do not support this hypothesis because the proportion
of patients who acquired a bacterial infection at any site and the proportion of patients
with ventilator-associated pneumonia were reduced by approximately 51% and 64%,
respectively, in patients with both early and late defecation.

The study has some limitations. The study was performed within a single ICU; the results
may therefore not be applicable to other ICUs, although the median time for passage of
stools in the present study was very similar to that reported by others.[4, 5] Because
abdominal examination with a stethoscope was not standardized, the absence of
abdominal sounds was not included in the analysis. Analysis of upper and lower digestive
tract distention through regularly-performed computed tomography scans and
confirmation of feces stasis through colonic examinations were beyond the scope of this
observational study.

In conclusion, in this study focusing on long-term ventilated patients, delayed defecation


was frequent. A SBP of <90 mm Hg and a Pao2/Fio2 ratio of <150 mm Hg during the first
5 days of MV were associated with an increased time needed to produce the first stool.
As shown by previous authors, constipation is associated with a longer duration of MV
and a longer stay in the ICU. In addition, we found that LOD scores and the proportion of
acquired bacterial infections were significantly higher in patients with delayed
defecation. Our results may help in the identification of patients with prolonged MV who
are at high risk for constipation and improve the care of these patients. It did not appear
that delayed defecation reduced the efficacy of selective decontamination of the digestive
tract. Delayed defecation was not associated with vomiting or higher gastric residual
volumes during the first days of MV.

[ CLOSE WINDOW ]

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The authors have not disclosed any potential conflicts of interest.

Crit Care Med. 2010;38(10):1933-1938. © 2010 Lippincott Williams & Wilkins