Ileus in critical illness: mechanisms and management

Anthony J. Bauer, PhD,* Nicolas T. Schwarz, MD, Beverley A. Moore, PhD,*

Andreas Trler, MD,* and Jrg C. Kalff, MD

Nonobstructive ileus, signifying the impairment of coordinated

propulsive intestinal motility, remains a frequently documented
and almost inevitable consequence of open abdominal surgery
and sepsis. Despite the frequency and major impact of ileus on
morbidity and mortality, the exact underlying molecular and
cellular mechanisms of this important clinical conundrum are
still ill defined. Animal models suggest that both neuronal and
local inflammatory responses within the intestinal muscularis
mechanistically contribute to intestinal ileus. The neuronal
mechanism appears to involve the enhanced release of nitric
oxide from inhibitory motor neurons. Likewise, nitric oxide and
prostaglandins are released from inflammatory cells
(macrophages and monocytes) via the induction of nitric oxide
synthase (iNOS) and cyclooxygenase-2. Recently, preliminary
data have confirmed the existence of an intraoperative local
muscularis inflammatory response during surgery in human
patients. Curr Opin Crit Care 2002, 8:152157 2002 Lippincott Williams &
Wilkins, Inc.

*Department of Medicine/Gastroenterology, University of Pittsburgh Medical

Center, Pittsburgh, Pennsylvania, USA; and Klinik und Poliklinik fr Allgemein-,
Viszeral-, Thorax- und Gefchirurgie, Rheinische Friedrich-Wilhelms-Universitt
Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
Correspondence to Anthony J. Bauer, PhD, Department of
Medicine/Gastroenterology, S-849 Scaife Hall, 3550 Terrace St., University of
Pittsburgh Medical School, Pittsburgh, PA 15261, USA; e-mail: tbauer+@pitt.edu
This work was supported by National Institutes of Health grants R01-GM-58241
and P50-GM-53789 and grants from the Deutsche Forschungsgemeinschaft (TU
116/2-1, SCHW 745/1-1, and KA 1270/1-1).
Current Opinion in Critical Care 2002, 8:152157
Abbreviations
iNOS
MCP
TNF

inducible nitric oxide synthase

monocyte chemoattractant protein
tumor necrosis factor

ISSN 10705295 2002 Lippincott Williams & Wilkins, Inc.

152

Postoperative ileus
As recognized by Canon and Murphy [1] in 1906, postoperative ileus is an obligatory feature after abdominal
surgery [2]. However, despite its normally benign
character, it is accompanied by a considerable increase in
morbidity and substantial hospitalization costs. Multiple
causes of postoperative ileus have been suggested, including the involvement of sympathetic reflexes, inhibitory humoral agents, norepinephrine release from the
bowel wall, anesthetic agents, and inflammation [3,4].
Since the introduction of laparoscopic techniques, reports have indicated that minimally invasive surgery is
accompanied by a much shorter period of postoperative
ileus, suggesting that the condition may be caused, in
part, by operative manipulation [59]. It is becoming apparent from rodent studies that at least two major mechanisms are involved in manipulation-induced postoperative ileus: neurogenic and inflammatory mechanisms.
These two mechanisms are thought to work cooperatively in causing postoperative ileus. However, the importance of each mechanism may vary over time, with
considerable overlap and possible interactions.
Neurogenic mechanisms of postoperative ileus

Tach et al. [10] developed an elegant, neuronally-based

hypothesis on ileus. In their scenario, cecal manipulation
results in the central release of corticotropin-releasing
factor in the paraventricular nucleus of the hypothalamus
and the dorsal vagal complex. This central neural activity
is then thought to stimulate an efferent inhibitory motor
pathway. The inhibitory efferent pathway appears to
consist of the activation of adrenergic and nonadrenergic,
noncholinergic motor neurons via both vagal and
splanchnic routes [11]. The enhanced release of the
prominent nonadrenergic, noncholinergic inhibitory
neuromuscular transmitter, nitric oxide, appears to play a
substantial role [12]. Evidence also suggests a role for the
inhibitory neurotransmitter vasoactive intestinal peptide
[13,14]. Because all studies investigating these neuronal
mechanisms were performed within the first hours after
surgery, these data primarily support the involvement of
neuronal mechanisms early after surgery. Additionally,
these studies have mostly focused on proximal bowel
motility, and the effective duration of ileus may be dependent primarily on the return of colonic motility [2].
Therefore, neural mechanisms are unlikely to be the sole
cause of postoperative ileus, which has a duration of several days [2,4,15].

Mechanisms of ileus in critical illness Bauer et al. 153

Inflammatory mechanisms of postoperative ileus

As a first step in understanding postoperative ileus, the

authors investigated the muscularis externa as a unique,
immunologically active compartment. Studies have demonstrated that within the normal muscularis externa lies
an impressive array of common leukocytes [16]. Most
often seen were resident macrophages, which form an
extensive network of cells from the esophagus to the
colon [1719]. Classically, macrophages function as sentinels and are protean-like cells that have the proclivity
to secrete a cornucopia of substances, notably cytokines,
nitric oxide, prostaglandins, reactive oxygen intermediates, and defensins [20,21]. In general, the authors studies have shown that surgical manipulation of the intestine activates the dense network of normally quiescent
macrophages to liberate the kinetically active substances
nitric oxide and prostaglandins through inducible nitric
oxide synthase (iNOS) and cyclooxygenase-2 [22,
23]. Intestinal manipulation also induces the secretion
of proinflammatory cytokines such as tumor necrosis factor (TNF)-, interleukin (IL)-1, IL-6, and monocyte
chemoattractant protein (MCP)-1, which upregulate adhesion molecules (eg, intercellular adhesion molecule-1)
on the muscularis vascular endothelium [24]. The data
demonstrate that after this local molecular inflammatory
response, a cellular inflammatory phase ensues with the
additional recruitment of circulating leukocytes (monocytes and neutrophils) into the muscularis externa [25]
and further release of nitric oxide, prostanoids, cytokines, reactive oxygen intermediates, and proteases
[24]. The important role of the kinetically active substances nitric oxide and prostaglandins in causing postoperative ileus has been confirmed using pharmacologic
and genetic approaches [22,23]. The cyclooxygenase-2 pathway has also been shown important in Trichinella-infected mice [26]. Additionally, monoclonal antibodies against intercellular adhesion molecule-1 and
the 2-integrins have been used to block leukocyte
recruitment after intestinal manipulation [24]. This
study demonstrated that attenuation of leukocyte recruitment prevents surgically-induced suppression in
muscle function.
Intestinal manipulation has also been demonstrated to
recruit mast cells into the intestinal muscularis [27]. The
activation of mast cells can be initiated by multiple
stimuli, including neuropeptides, cytokines, histaminereleasing factors, bacteria, and bowel manipulation [28
30]. Once activated, these cells frequently degranulate
and release potent preformed proinflammatory mediators (such as TNF-, histamine, and proteases) and produce newly synthesized mediators (prostaglandins,
platelet activating factor) and a variety of cytokines
[31,32]. Mast cell activation can amplify the recruitment
of leukocytes through the release of histamine and the
upregulation of adhesion molecules [33,34]. In other
studies, the direct modulation of gastrointestinal motility

by deregulating mast cells has been demonstrated to be

dependent on the release of serotonin and prostaglandins
[35]. Hypothetically, mast cells could also play an important mechanistic role in postoperative ileus.
Recently, the authors have generated supportive data
that the local molecular and cellular inflammatory
responses within the muscularis may be compounded by
the enteric transference of luminal substances, which
are preferentially picked up by the intestinal lymphatic
system and activate leukocytes that subsequently invade the primed vascular beds within the manipulated
intestinal muscularis [36,37]. Although still hypothetical, the cytokines secreted from the muscularis externa
generated after surgery could also modulate enteric neuronal function. Collins et al. [38] and Galeazzi et al. [39]
have convincingly shown that macrophage-derived cytokines can alter the release of enteric neuromuscular
transmitters.
The clinical relevance of many of these findings in rodents has recently been confirmed in surgical specimens
obtained from patients undergoing intestinal resection.
In these preliminary studies, human small bowel specimens were obtained at two time points during abdominal
surgery: early specimens at less than 60 minutes after
incision, and late specimens at more than 3 hours after
incision. The total RNA of the isolated muscularis was
extracted, and semiquantitative reverse transcription
polymerase chain reaction was used to measure iNOS,
cyclooxygenase-2, and IL-6 mRNA levels. These experiments demonstrated that, as in the rodent model, inflammatory mRNA-levels were considerably increased intraoperatively within the muscularis of patients undergoing
intestinal surgery [40,41].
Management of postoperative ileus

Although sympathetic hyperactivity has been implicated

as an important component of postoperative ileus, a recent pharmacologic study in humans using propranolol
did not notably improve perioperative electromyographic
patterns after -adrenergic blockade in patients exhibiting ileus [42]. Animal studies have suggested that prokinetic agents might be effective treatments of postoperative ileus [43]. However, current prokinetics primarily
alter upper gastrointestinal motility and generally have
not been effective for postoperative ileus [44,45]. However, recently, the prokinetic, antiacetylcholinesterase
properties of neostigmine are emerging as a reasonably
successful treatment for acute relief from the symptoms
of postoperative ileus [46,47,48], drug overdose [49],
and critically ill-related colonic ileus [50]. In this doubleblind, placebo-controlled study of 24 critically ill patients, a prolonged continuous infusion of neostigmine
(0.4 mg/h) resulted in the passage of stools in 79% of the
patients, whereas none of the patients receiving placebo
passed stools. The investigators also commented that the

154 Gastrointestinal system

neostigmine infusion did not have to be stopped in any

of the patients as a result of a major adverse effect. This
is in contrast to bolus injections of neostigmine (2 mg) in
patients with Ogilvie syndrome who occasionally develop symptomatic bradycardia. Animal studies have also
suggested a role for peripherally located opioid receptors
in the pathogenesis postoperative ileus [51]. Human
studies using a selective opioid antagonist have supported the use of the investigational drug ADL 82698
(Adolor, Exton, PA) for postoperative motility dysfunction [52,53]. Recently, multimodal rehabilitation (epidural analgesia, early oral nutrition and mobilization, and
laxative) has been reported to hasten postoperative
bowel recovery [2,54]. However, no accepted pharmacologic prevention or treatment of postoperative ileus
currently exists, so treatment remains mostly supportive,
consisting of the administration of intravenous fluids and
nasogastric suction. Ideally, insights into the importance
of the inflammatory events associated with postoperative
ileus will lead to effective pharmacologic prevention or
management of this iatrogenic complication of surgery.

Sepsis-induced ileus
Sepsis-induced ileus after complicated abdominal surgery, hemorrhagic shock, trauma, and burns still causes
morbidity and mortality in the critically ill [55]. It can be
predicted that as advances in life-support strategies continue to improve, endotoxemia will increasingly impact
the treatment of the seriously ill patient. There is increasing evidence that intestinal barrier failure and bacterial translocation play a major role in the development
of sepsis. In fact, frequently the source of the contaminating bacteria can be traced to the endogenous flora of
the gastrointestinal tract [56,57].
The intestine also is one of the target organs in the sequelae of sepsis. The induction of sepsis in experimental
animals by the systemic administration of live bacteria or
endotoxin has a detrimental effect on the metabolic and
barrier functions of the small intestine, furthering the
translocation of bacteria or its products [58,59,60,61].
Along with mucosal dysfunction, endotoxemia is known
to be associated with alterations in gastrointestinal motility. It has been shown that a single, sublethal dose of
endotoxin temporarily disrupts gastrointestinal motility
and transit [62,6365,66]. Furthermore, gastrointestinal stasis may result in luminal bacterial overgrowth,
producing a further source of bacterial products that
cause ileus and mucosal dysfunction.
It has recently been reported that a dense network of
resident macrophages, which appear to be inactive in
their basal state [18], populates the intestinal muscularis
[16,18]. However, endotoxin rapidly activates these resident intestinal macrophages, and they subsequently initiate a molecular and cellular inflammatory response that
causes intestinal dysmotility [66,67]. Lipopolysaccha-

ride-activated macrophages are able to secrete a plethora

of biologically active substances into their local milieu
[68]. Some of these substances act as chemokines and
cytokines by initiating subsequent inflammatory reactions, which can further potentiate gastrointestinal dysmotility. The authors have shown that exogenous lipopolysaccharide causes the extravasation of leukocytes
into the intestinal muscularis, which consists mainly of
monocytes, polymorphonuclear neutrophils, and mast
cells [69].
The intestinal muscularis, particularly the resident macrophages, has been demonstrated to secrete MCP-1 in
response to lipopolysaccharide and a wide range of cytokines such as IL-6, TNF-, and IL-1 [70,71]. MCP-1 is
a potent chemoattractant capable of promoting monocyte
recruitment into an inflammatory site and activating
monocytes and macrophages [72,73]. Interestingly, IL-6,
TNF-, and IL-1 are also known to be released
within the gut wall during endotoxemia [74] and could
cause an intensified expression of MCP-1. Trler et al.
[75] recently demonstrated a seminal role for MCP-1 by
showing that exogenous MCP-1 application to the bowel
wall in vivo caused a massive recruitment of monocytes
into the muscularis, and that antibody neutralization of
endogenous MCP-1 substantially decreased leukocyte
extravasation into the muscularis and abrogated lipopolysaccharide-induced ileus.
However, MCP-1 appears to play a Janus-faced role in
rodents. In contrast to the beneficial effects of MCP-1
blockade on ileus, previous studies have reported that
antiMCP-1 antibodies were detrimental during lethal
endotoxemia and cecal-derived bacteria contamination
[76,77]. It appears that when endotoxin is used in a normally lethal concentration, the ability of MCP-1 to induce anti-inflammatory cytokines (ie, IL-10) may be essential to limit mortality [78]. Likewise, in a cecal
ligation puncture model of sepsis, MCP-1 limited bacterial spread and induced anti-inflammatory cytokines,
both of which would benefit survival [77,79]. However,
the same chemotactic ability of MCP-1 that potentially
limits bacterial spread appears to play a substantial role
in lipopolysaccharide-recruited, monocyte/macrophageinduced intestinal ileus.
Studies by Eskandari et al. [80] and Trler et al. [75]
support the hypothesis that leukocytes within the intestinal muscularis suppress gastrointestinal motility during
endotoxemia. Activated monocytes and polymorphonuclear neutrophils are able to secrete numerous cytokines and kinetically active substances such as nitric oxide, prostaglandins, reactive oxygen, and nitrogen
intermediates. Experimental studies have clearly shown
that nitric oxide from iNOS upregulated monocytes/macrophages functions as a major suppressor of circular
smooth muscle contractility during endotoxemia [81,82].

Mechanisms of ileus in critical illness Bauer et al. 155

Furthermore, it has been reported that superoxide radicals secreted from activated polymorphonuclear neutrophils have a direct impact on smooth muscle tone
[83,84]. It is also known that prostaglandins have an inhibitory effect on intestinal smooth muscle cells [85,86].
Supporting a role for prostaglandins during sepsisinduced ileus is a study demonstrating that lipopolysaccharide induces cyclooxygenase-2 expression within the
intestinal muscularis macrophages, and that the local
generation of prostaglandins may enhance lipopolysaccharide-induced iNOS expression in an autocrine manner, with both substances acting synergistically to cause
inhibition of intestinal circular smooth muscle contractility [87]. A further enhancement of iNOS expression
appears to come from the lipopolysaccharide-induced
generation of TNF- and IL-1 (IL-1): TNF binding
protein and IL-1 receptor antagonist-treated rats prevented the lipopolysaccharide-induced decrease in
muscle contractility and substantially decreased the escalated expression of iNOS by lipopolysaccharide [66].

12

As with postoperative ileus, there is no accepted pharmacologic prevention or management of septic-induced

ileus. Therefore, management remains largely supportive. Insights gained by studying sepsis-induced muscularis inflammatory events may help produce an effective
pharmacologic prevention or management strategy.

References and recommended reading

Papers of particular interest, published within the annual period of review,
have been highlighted as:

Of special interest

Of outstanding interest
1

Cannon WB, Murphy FT: The movement of the stomach and intestine in some
surgical conditions. Ann Surg 1906, 43:512536.

2
Holte K, Kehlet H: Postoperative ileus: a preventable event. Br J Surg 2000,
87:14801493.

An excellent review on the current status of postoperative ileus, covering mechanisms and therapeutic management strategies.

De Winter BY, Boeckxstaens GE, De Man JG, et al.: Effect of adrenergic and
nitrergic blockade on experimental ileus in rats. Br J Pharmacol 1997,
120:464468.

13

Boeckxstaens GE, Hollmann M, Heisterkamp SH, et al.: Evidence for

VIP(1)/PACAP receptors in the afferent pathway mediating surgery-induced
fundic relaxation in the rat. Br J Pharmacol 2000, 131:705710.
A continuing series of excellent articles by the Antwerp group investigating the
influences of neuronal activation after intestinal manipulation.
14

De Winter BY, Robberecht P, Boeckxstaens GE, et al.: Role of VIP1/PACAP

receptors in postoperative ileus in rats. Br J Pharmacol 1998, 124:1181
1186.

15

Reissman P, Agachan F, Wexner SD: Outcome of laparoscopic colorectal

surgery in older patients. Am Surg 1996, 62:10601063.

16

Kalff JC, Schwarz NT, Walgenbach KJ, et al.: Leukocytes of the intestinal
muscularis externa: their phenotype and isolation. J Leukoc Biol 1998,
63:683691.

17

Bauer AJ: Transplantation-induced injuries to the intestinal muscularis and its

innervation: from preservation to chronic rejection. Transplant Proc 1996,
28:25392541.

18

Mikkelsen HB: Macrophages in the external muscle layers of mammalian intestines. Histol Histopathol 1995, 10:719736.

19

Faussone-Pellegrini MS, Pantalone D, Cortesini C: Smooth muscle cells, interstitial cells of Cajal and myenteric plexus interrelationships in the human
colon. Acta Anatomica 1990, 139:3144.

20

Kagan BL, Ganz T, Lehrer RI: Defensins: a family of antimicrobial and cytotoxic peptides. Toxicology 1994, 87:131149.

21

Cicalese L, Rastellini C, Rao AS, et al.: Pyruvate prevents mucosal reperfusion injury, oxygen free-radical production, and neutrophil infiltration after rat
small bowel preservation and transplantation. Transplant Proc 1996,
28:2611.

22

Kalff JC, Schraut WH, Billiar TR, et al.: Roles of inducible nitric oxide synthase
in postoperative intestinal smooth muscle dysfunction in rodents. Gastroenterology 1999, 188:316327.
Nitric oxide is known to modulate intestinal muscle contractility as an inhibitory
neuromuscular transmitter, but in this study, the important kinetic properties of
nitric oxide are also demonstrated when it is released from resident and recruited
leukocytes from the inducible form of nitric oxide synthase. This study used both
pharmacologic and genetically deficient iNOS mice to demonstrate the importance
of nitric oxide as induced by intestinal manipulation.
23

Schwarz NT, Kalff JC, Trler A, et al.: Prostanoid production via COX-2 as a
causative mechanism of rodent postoperative ileus. Gastroenterology 2001,
121:13541371.
Prostaglandins could be the most potent kinetically active substances on intestinal
smooth muscle. The researchers, by using selective cyclooxygenase-2 inhibition
with 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone
(DFU) and genetically deficient cyclooxygenase-2 mice, demonstrated an important role for the induction of cyclooxygenase-2 by intestinal manipulation in rodents.
24

Kalff JC, Carlos TM, Schraut WH, et al.: Surgically induced leukocytic infiltrates within the rat intestinal muscularis mediate postoperative ileus. Gastroenterology 1999, 117:378387.
The role of recruited leukocytes in causing prolonged intestinal ileus after surgical
manipulation of the intestine is directly demonstrated using adhesion molecular
blocking antibodies.

Bueno L, Ferre JP, Ruckebusch Y: Effects of anesthesia and surgical procedures on intestinal myoelectric activity in rats. Dig Dis 1978, 23:690695.

Livingston EH, Passaro EP Jr: Postoperative ileus. Dig Dis Sci 1990,
35:121132.

Dubois F, Icard P, Berthelot G, et al.: Coelioscopic cholecystectomy: preliminary report of 36 cases. Ann Surg 1990, 211:6062.

Garcia-Caballero M, Vara-Thornbeck C: The evolution of postoperative ileus

after laparoscopic cholecystectomy. Surg Endosc 1993, 7:416419.

Ludwig KA, Frantzides CT, Carlson MA, et al.: Myoelectric motility patterns
following open versus laparoscopic cholecystectomy. J Laparoendosc Surg
1993, 3:461466.

Schippers E, Ottinger AP, Anurov M, et al.: Laparoscopic cholecystectomy: a

minor abdominal trauma? World J Surg 1993, 17:539543.

Bhm B, Milsom JW, Fazio VW: Postoperative intestinal motility following

conventional and laparoscopic intestinal surgery. Arch Surg 1995, 130:415
419.

27

Kalff JC, Schraut WH, Simmons R, et al.: Surgical manipulation of the gut
elicits an intestinal muscularis inflammatory response resulting in postoperative ileus. Ann Surg 1998, 228:652663.

10

Tach Y, Monnikes H, Bonaz B, et al.: Role of CRF in stress-related alterations

of gastric and colonic motor function. Ann N Y Acad Sci 1993, 697:233
243.

28

Collins SM, Marzio L, Vermillion DL, et al.: The immunomodulation of gut motility: factors that determine the proliferation of mast cells in the sensitized gut
[abstract]. Gastroenterology 1988, 94:A74.

11

Boeckxstaens GE, Hirsch DP, Kodde A, et al.: Activation of an adrenergic and

vagally-mediated NANC pathway in surgery-induced fundic relaxation in the
rat. Neurogastroenterol Motil 1999, 11:467474.

29

Malaviya R, Ross E, Jakschik BA, et al.: Mast cell degranulation induced by

Type 1 fimbriated Escherichia coli in mice. J Clin Invest 1994, 93:1645
1653.

25

Kalff JC, Eskandari MK, Hierholzer C, et al.: Biphasic response to gut manipulation and temporal correlation of cellular infiltrates and muscle dysfunction in
rat. Surgery 1999, 126:498509.

26

Barbara G, De Giorgio R, Deng Y, et al.: Role of immunologic factors and

cyclooxygenase 2 in persistent postinfective enteric muscle dysfunction in
mice. Gastroenterology 2001, 120:17291736.
Longitudinal smooth muscle and circular smooth muscle of the intestine respond in
an opposite manner to certain prostanoids. For example, PGE2 increases longitudinal muscle contractility but inhibits circular muscle contractility. Therefore, it is not
surprising that in this study using the nematode model, the postinfective activation
of cyclooxygenase-2 in resident cells of the muscularis externa contributes to longitudinal muscle hypercontractility.

156 Gastrointestinal system

30

Coleman JW, Holliday MR, Kimber I, et al.: Regulation of mouse peritoneal

mast cell secretory function by stem cell factor, IL-3 or IL-4. J Immunol 1993,
150:556562.

31

Galli SJ, Gordon JR, Wershil BK: Cytokine production by mast cells and basophils. Curr Opin Immunol 1991, 3:865873.

32

Wershil BK: Role of mast cells and basophils in gastrointestinal inflammation.

Chem Immunol 1995, 62:204238.

33

Kubes P, Kanwar S: Histamine induces leukocyte rolling in post-capillary venules: a P-selectin-mediated event. J Immunol 1994, 152:35703577.

34

Wershil BK, Furuta GT, Wang ZS, et al.: Mast cell-dependent neutrophil and
mononuclear cell recruitment in immunoglobulin E-induced gastric reactions
in mice. Gastroenterology 1996, 110:14821490.

35

Scott RB, Maric M: Mediation of anaphylaxis-induced jejunal circular smooth

muscle contraction in rats. Dig Dis Sci 1993, 38:396402.

36

Schwarz NT, Simmons RL, Bauer AJ: Minor intraabdominal injury followed by
low dose LPS administration act synergistically to induce ileus [abstract].
Neurogastroenterol Motil 2000, 11:288.

Schwarz NT, Beer-Stolz D, Simmons RL, et al.: Pathogenesis of paralytic

ileus: intestinal manipulation opens a transient pathway between the intestinal
lumen and the leukocytic infiltrate of the jejunal muscularis. Ann Surg 2002,
235:3140.
This study provides a crucial link to studies on translocation and the inflammatory
response generated within the muscularis of the manipulated intestine. These data
show that intestinal manipulation leads to a transient increase in mucosal permeability and that the extraintestinal endocytotic uptake of transferred particles by
circulating monocytes precedes their infiltration into the gut wall. The transference
of luminal bacterial products may follow a route and time course similar to that of the
microspheres. The researchers hypothesize that endogenous bacterial products
act synergistically with the inflammatory response within the postsurgical intestinal
muscularis, leading to an exacerbation of postoperative ileus.

postoperative ileus in orthopedic spinal patients. J Spinal Disord 2001,

14:541545.
49

Isbister GK, Oakley P, Whyte I, et al.: Treatment of anticholinergic-induced

ileus with neostigmine. Ann Emerg Med 2001, 38:689693.

50

van der Spoel JI, Oudemans-van Straaten HM, Stoutenbeek CP, et al.: Neostigmine resolves critically illness-related colonic ileus in intensive care patients with multiple organ failure: a prospective, double-blind, placebocontrolled trial. Intensive Care Med 2001, 27:822827.

51

De Winter BY, Boeckxstaens GE, De Man JG, et al.: Effects of mu- and
kappa-opioid receptors on postoperative ileus in rats. Eur J Pharmacol 1997,
339:6367.

52 Taguchi A, Sharma N, Saleem RM, et al.: Selective postoperative inhibition of

gastrointestinal opioid receptors. N Engl J Med 2001, 345:935940.

Opioids are known to decrease inhibitory neuromuscular transmission. Adolor (Exton, PA) has designed an opioid antagonist to offset the untoward gastrointestinal
effects of endogenously released and therapeutic opioids for postsurgical pain.
53

37

38

Collins SM, Hurst SM, Main C, et al.: Effect of inflammation of enteric nerves:
cytokine-induced changes in neurotransmitter content and release. Ann N Y
Acad Sci 1992, 664:415424.

Galeazzi F, Haapala EM, Van Rooijen N, et al.: Inflammation-induced impairment of enteric nerve function in nematode-infected mice is macrophage dependent. Am J Physiol Gastrointest Liver Physiol 2000, 278:G259G265.
This study continues the excellent and long-standing series of studies using the
nematode model. These data show that depletion of resident muscularis macrophages using liposomes containing the toxin dichloromethylene diphosphonate
(clodronate) prevented the infection-induced suppression in acetylcholine release.
These data show the involvement of the resident macrophage network in the functional impairment of enteric cholinergic nerves.

54

Basse L, Madsen J, Kehlet H: Normal gastrointestinal transit after colonic

resection using epidural analgesia, enforced oral nutrition and laxative. Br J
Surg 2001, 88:14981500.
This group has shown that aggressive postsurgical treatment of the patient with
combinatorial therapy is effective in reducing time to defecation after surgery.
55

Anning PB, Evans TW: Leukocytes in sepsis: do they just keep rolling along?
[editorial]. Crit Care Med 2000, 28:31083109.

56

Deitch EA, Rutan R, Waymack JP: Trauma, shock, and gut translocation. New
Horiz 1996, 4:289299.

57

OBoyle CJ, MacFie J, Mitchell CJ, et al.: Microbiology of bacterial translocation in humans. Gut 1998, 42:2935.

58

ODwyer ST, Michie HR, Ziegler TR, et al.: A single dose of endotoxin increases intestinal permeability in healthy humans. Arch Surg 1988,
123:14591464.

59

Hutcheson IR, Whittle BJ, Boughton-Smith NK: Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the
rat. Br J Pharmacol 1990, 101:815820.

39

40

Kalff JC, Eskandari MK, Hierholzer C, et al.: Selective coinduction of cyclooxygenase-2 and inducible nitric oxide synthase in human intestinal smooth
muscle during abdominal surgery [abstract]. Gastroenterology 1998,
114:A774.
These data provide evidence that the human surgically manipulated intestinal muscularis responds in a manner similar to that of rodents.
41

Kalff JC, Eskandari MK, Hierholzer C, et al.: IL-6 expression in activated resident muscularis macrophages of the human small intestine after abdominal
surgery [abstract]. Gastroenterology 1997, 112:A1159.

42 Ferraz AA, Wanderley GJ, Santos MA Jr, et al.: Effects of propranolol on

human postoperative ileus. Dig Surg 2001, 18:305310.

An important study in humans showing that -adrenergic blockade is not effective

in treating postoperative ileus.
43

De Winter BY, Boeckxstaens GE, De Man JG, et al.: Effect of different prokinetic agents and a novel enterokinetic agent on postoperative ileus in rats.
Gut 1999, 45:713718.

44

Bungard TJ, Kale-Pradhan PB: Prokinetic agents for the treatment of postoperative ileus in adults: a review of the literature. Pharmacotherapy 1999,
19:416423.

45

Seta ML, Kale-Pradhan PB: Efficacy of metoclopramide in postoperative ileus

after exploratory laparotomy. Pharmacotherapy 2001, 21:11811186.

46

Trevisani GT, Hyman NH, Church JM: Neostigmine: safe and effective treatment for acute colonic pseudo-obstruction. Dis Colon Rectum 2000,
43:599603.

Kreis ME, Kasparek M, Zittel TT, et al.: Neostigmine increases postoperative

colonic motility in patients undergoing colorectal surgery. Surgery 2001,
130:449456.
Neostigmine, through its antiacetylcholinesterase properties, stimulates colonic
contractions, possibly affording temporary symptomatic relief from postoperative
ileus.

60 Moore FA: The role of the gastrointestinal tract in postinjury multiple organ
failure. Am J Surg 1999, 178:449453.

A good review on the role of the gastrointestinal tract in multiple organ failure.
61

Althausen PL, Gupta MC, Benson DR, et al.: The use of neostigmine to treat

Fink MP: Does tissue acidosis in sepsis indicate tissue hypoperfusion? Intensive Care Med 1996, 22:11441146.

62

Eskandari MK, Kalff JC, Billiar TR, et al.: LPS-induced muscularis macrophage
nitric oxide suppresses rat jejunal circular muscle activity. Am J Physiol 1999,
277:G478G486.
Macrophages are known to secrete copious amounts of nitric oxide in response to
lipopolysaccharide. These data show that the dense network of resident macrophages within the normal muscularis is similar in this regard to other macrophage
populations, and that the induction of iNOS and the liberation of nitric oxide have a
local inhibitory paracrine effect on the adjacent smooth muscle cells of the muscularis externa.
63

Cullen JJ, Caropreso DK, Ephgrave KS: Effect of endotoxin on canine gastrointestinal motility and transit. J Surg Res 1995, 58:9095.

64

Cullen JJ, Ephgrave KS, Caropreso DK: Gastrointestinal myoelectric activity

during endotoxemia. Am J Surg 1996, 171:596599.

65

Weisbrodt NW, Pressley TA, Li Y, et al.: Decreased ileal muscle contractility

and increased NOS II expression induced by lipopolysaccharide. Am J Physiol 1996, 271:G454G460.

66

Lodato RF, Khan AR, Zembowicz MJ, et al.: Roles of IL-1 and TNF in the
decreased ileal muscle contractility induced by lipopolysaccharide. Am J
Physiol Gastrointest Liver Physiol 1999, 276:G1356G1362.
TNF and IL-1 are shown to play a role in the induction of iNOS and the subsequent
inhibition of smooth muscle contractility.
67

Torihashi S, Ozaki H, Hori M, et al.: Resident macrophages activated by lipopolysaccharide suppress muscle tension and initiate inflammatory response
in the gastrointestinal muscle layer. Histochem Cell Biol 2000, 113:7380.

68

Nathan CF: Secretory products of macrophages. J Clin Invest 1987,

79:319326.

69

Eskandari MK, Kalff JC, Billiar TR, et al.: Lipopolysaccharide activates the
muscularis macrophage network and suppresses circular smooth muscle activity. Am J Physiol 1997, 273:G727G734.

47

48

Liu SS, Hodgson PS, Carpenter RL, et al.: ADL 82698, a trans-3,4-dimethyl4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther 2001,
69:6671.

Mechanisms of ileus in critical illness Bauer et al. 157

70

Brieland JK, Flory CM, Jones ML, et al.: Regulation of monocyte chemoattractant protein-1 gene expression and secretion in rat pulmonary alveolar macrophages by lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-1 beta. Am J Respir Cell Mol Biol 1995, 12:104109.

71

Coletta I, Soldo L, Polentarutti N, et al.: Selective induction of MCP-1 in human mesangial cells by the IL-6/sIL- 6R complex. Exp Nephrol 2000,
8:3743.

72

Fuentes ME, Durham SK, Swerdel MR, et al.: Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of
monocyte chemoattractant protein-1. J Immunol 1995, 155:57695776.

73

Leonard EJ, Yoshimura T: Human monocyte chemoattractant protein-1

(MCP-1). Immunol Today 1990, 11:97101.

74

Villa P, Sartor G, Angelini M, et al.: Pattern of cytokines and pharmacomodulation in sepsis induced by cecal ligation and puncture compared with that
induced by endotoxin. Clin Diagn Lab Immunol 1995, 2:549553.

Trler A, Schwarz NT, Trler E, et al.: MCP-1 causes leukocyte recruitment

and subsequently endotoxemic ileus in rat. Am J Physiol Gastrointest Liver
Physiol 2001, 282:G145G155.
The chemokine MCP-1, produced from the resident muscularis macrophage, is
shown to play a role mechanistically in the recruitment of monocytes into the intestinal muscularis. The recruited leukocytes then inhibit muscle contractility by the
secretion of kinetically active substances such as nitric oxide and prostaglandins.

chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic

peritonitis: cross-talk between MCP-1 and leukotriene B4. J Immunol 1999,
163:61486154.
80

Eskandari MK, Kalff JC, Billiar TR, et al.: Lipopolysaccharide activates the
muscularis macrophage network and suppresses circular smooth muscle activity. Am J Physiol 1997, 273:G727G734.

81

Eskandari MK, Kalff JC, Billiar TR, et al.: LPS-induced muscularis macrophage
nitric oxide suppresses rat jejunal circular muscle activity. Am J Physiol 1999,
277:G478G486.

82

Torihashi S, Ozaki H, Hori M, et al.: Resident macrophages activated by lipopolysaccharide suppress muscle tension and initiate inflammatory response
in the gastrointestinal muscle layer. Histochem Cell Biol 2000, 113:7380.

83

Granger DN: Role of xanthine oxidase and granulocytes in ischemiareperfusion injury. Am J Physiol 1988, 255:H1269H1275.

84

Mehta JL, Lawson DL, Nicolini FA, et al.: Effects of activated polymorphonuclear leukocytes on vascular smooth muscle tone. Am J Physiol 1991,
261:H327H334.

85

Botella A, Delvaux M, Fioramonti J, et al.: Stimulatory (EP1 and EP3) and

inhibitory (EP2) prostaglandin E2 receptors in isolated ileal smooth muscle
cells. Eur J Pharmacol 1993, 237:131137.

86

Sanders KM: Endogenous prostaglandin E and contractile activity of isolated

ileal smooth muscle. Am J Physiol 1978, 234:E209E212.

75

76

Zisman DA, Kunkel SL, Strieter RM, et al.: MCP-1 protects mice in lethal
endotoxemia. J ClinInvest 1997, 99:28322836.

77

Matsukawa A, Hogaboam CM, Lukacs NW, et al.: Endogenous MCP-1 influences systemic cytokine balance in a murine model of acute septic peritonitis.
Exp Mol Pathol 2000, 68:7784.

78

Zisman DA, Kunkel SL, Strieter RM, et al.: MCP-1 protects mice in lethal
endotoxemia. J Clin Invest 1997, 99:28322836.

79

Matsukawa A, Hogaboam CM, Lukacs NW, et al.: Endogenous monocyte

87

Hori M, Kita M, Torihashi S, et al.: Upregulation of iNOS by COX-2 in muscularis resident macrophage of rat intestine stimulated with LPS. Am J Physiol
Gastrointest Liver Physiol 2001, 280:G930G938.
This study finds that lipopolysaccharide increases iNOS and cyclooxygenase-2
expression and stimulates nitric oxide and prostaglandin production in muscularis
resident macrophages, resulting in the inhibition of intestinal smooth muscle contraction. Furthermore, their data suggest that lipopolysaccharide-induced iNOS
gene expression may be modulated by the local upregulation of the cyclooxygenase-2 gene and prostaglandin release.