RESULTS
A total of 35 dogs were evaluated, with 19 in the treatment group receiving
oseltamivir and 16 in the control group receiving a placebo. There were 3 shelter dogs
included in the study, all of which were in the control group. Most dogs (30/35) were of
the mixed-breed variety, with the purebreds consisting of 2 American pit bull terriers and
1 each of dachshund, beagle, and Labrador retriever. No statistically significant
differences were found between groups in the baseline characteristics of age, sex,
vaccination status or duration of clinical signs prior to presentation. The median age of
dogs in the control group was 14 (8, 36) weeks, while that of the treatment group was 12 (8, 44) weeks (p=0.50). There were 21 (60%) female dogs, with 10 (48%) randomized to
the control group and 11 (52%) randomized to the treatment group. Alternatively, there
were 14 (40%) male dogs, with 6 (43%) randomized to the control group and 8 (57%) to
the treatment group (p=1.0). All dogs were sexually intact. Vaccination status was
known for 10/16 (62%) dogs in the control group and 13/19 (68%) dogs in the treatment
group. Of these, 5 (50%) dogs in the control group had received at least one vaccination
against CPV, whereas 6 (46%) in the treatment group had been vaccinated at least once
against CPV (p=1.0). The duration of clinical signs prior to presentation was known for
15/16 (94%) control dogs and 16/19 (84%) treatment dogs. Mean days sick for the
control group was 1.4 (+/-0.9) days, while that for the treatment group was 1.8 (+/-1.0)
days (p=0.31).
There was no significant difference in the degree of estimated dehydration at
entry of dogs between groups. The control dogs were estimated to have a mean
dehydration deficit of 6.3% (+/-1.54%), while the treatment dogs were estimated at 6.9%
(+/-1.7%) (p=0.35). In addition, there was no statistical difference amongst the weights
at entry or the weights at discharge between the two groups. Dogs in the control group
had a median entry weight of 6.7kg (14.7lb) (1.8, 28.2kg [3.96, 62lb]), and those of the
treatment group 4kg (8.8lb) (1.6, 25kg [3.5, 55lb]) (p=0.21). At discharge, the median
weight of control dogs was 6.5kg (14.3lb) (1.8, 27.3kg [3.96, 60lb]) and that of the
treatment group was 4.4kg (9.7lb) (1.6, 28.6kg [3.5, 63lb]) (p=0.42). However, a
significant difference was found in the weight change from entry until discharge.
Dogs
in the control group experienced a median change of -0.21kg (-0.46lb) (-2.8, 0.5kg [-6.2,
1.1lb]), while those in the treatment group had a median gain of 0.07kg (0.15lb) (-1, percentage of change in body weight ([discharge weight ñ entry weight / entry weight] *
100%) (Figure 1). Dogs in the control group had a mean change of -4.5% (+/- 6.9%), and
those in the treatment group a mean change of +2.6% (+/- 7.1%) (p=0.006). When this
analysis was repeated for survivors only, the results were still found to be significant.
The control dogs contained all 3 non-survivors, and the new calculation without these
dogs resulted in a median percent weight change of -3.9% (-2.8, 0.5), compared to the
median percent weight change of 1.3% (-1, 3.6) for the treatment dogs (p=0.012).
The percentage of days in the hospital that SIRS criteria were met was calculated
for each dog. There was no significant difference between groups, with control dogs
meeting SIRS criteria a mean of 52% of days, versus 54% for treatment dogs (p=0.91).
No difference was found in the duration of hospitalization between the two
groups. Dogs in the control group had a mean stay of 5.9 (+/- 2.6) days, and those of the
treatment group 6.0 (+/- 2.3) days (p=1.0). Colloid therapy was not required often, as the
median number of days on colloids for the control group was 0 (0, 3) days and also 0 (0,
5) days for the treatment group (p=0.5). None of the 16 dogs in the control group
received a blood transfusion, while 2/19 (10%) dogs in the treatment group did (p=0.5).
The addition of chlorpromazine was necessary in 10/19 (53%) dogs in the treatment
group, and 9/16 (56%) dogs in the control group. Dogs in the treatment group that did
receive chlorpromazine did so an average of 21% of their days in the hospital, while the
dogs requiring it in the control group were given chlorpromazine an average of 30% of
their days in the hospital. The overall survival rate was 91% (32/35). Three dogs died,
all from the control group, giving this group a survival rate of 81% (13/16). One animal was euthanized after severe progression of clinical signs despite treatment, and it was
deemed that the dog was suffering and would not recover, while the other 2 suffered
natural deaths. Survival in the treatment group was 100% (19/19). However, this
difference was not found to be significant (p=0.09).
Post mortem examinations were performed on all non-surviving dogs. Findings
were consistent with a diagnosis of CPV enteritis.
All dogs had diffuse, severe,
necrotizing enteritis. Bone marrow was examined in 2/3 dogs, both showing sections of
moderate hypocellularity. While 2 dogs were noted to have diffuse congestion and
edema in their lungs, the third dog was found to have a mild interstitial pneumonia.
The white blood cell values that were evaluated (initial counts for WBC,
neutrophils and lymphocytes, the nadir values and day of nadir, and significant decreases
in counts for WBC, neutrophils and lymphocytes), were compared between groups. No
significant differences were found for any of these values between groups. Although it
was not found to be significant, it was noted that the treatment dogs had a very slightly
lower average WBC (7,500 cells/ul) and neutrophil count (6,220 cells/ul) at presentation
than the control dogs (8,540 cells/ul WBC and 6,830 cells/ul neutrophils). Both groups
experienced a decline in numbers with an average nadir of WBC at 2,680 and 2,810
cells/ul for the treatment and control groups, respectively, and 1,160 and 1,240 cells/ul
for the neutrophils for the treatment and control groups, respectively. While by Day 5 the
control dogs had rebounded their WBC (4,580 cells/ul) and neutrophil counts (2,270
cells/ul), the treatment dogs showed a slightly higher value for each at the same time
point (6,920 cells/ul WBC and 4,310 cells/ul neutrophils). Seven of the 16 (44%) control
dogs had a total WBC nadir occur at less than 100 cells/ul. Two of these 7 (29%) dogs did not survive (1 died, 1 euthanized). In the treatment group, 8/19 (42%) dogs had their
total WBC nadir occur at less than 100 cells/ul. None of these dogs died.
Comparison of significant decreases in white blood cells, neutrophils and
lymphocytes on initial presentation and on Day 4 of hospitalization is shown in Figure 2.
Based on the expected timeline of disease progression as previously described,11 Day 4
was chosen for this comparison to represent a period in time that should have
encompassed neutrophil and clinical recovery for most dogs. In general, a higher
percentage of treatment dogs versus control dogs fulfilled the criteria for significant
decreases in initial white blood cells and neutrophil counts. However, by Day 4, more
control dogs were significantly affected.
When the clinical scores were compared day by day for each category as well as
the cumulative total for that day, no significant differences were found between groups
(Figures 3) with the exception of Day 6 for the appetite score (p=0.02). There was also a
difference for attitude on Day 6, but this was not significant (p=0.086). Looking at the
scores for dogs in each group as compared to their white blood cell counts on the same
day (Table 2), it can be seen that the treatment dogs did have mildly improved scores
across the board on Days 4 and 5 while also having a quicker rebound of WBC and
neutrophil counts. Days 4 and 5 were chosen for examination for the same reason as
stated above.
DISCUSSION
Findings
While the use of oseltamivir in addition to standard therapy for naturally occurring CPV
enteritis did not exhibit a significant effect to help decrease hospitalization time,
additional treatments needed or disease morbidity as determined by a clinical scoring
system, it was shown to be associated with a significant increase in weight change versus
control dogs from entry until discharge. The control dogs tended to lose weight, while
the treatment dogs gained. This finding was not affected by the degree of dehydration at
presentation, as it was found that there was no significant difference between the two
groups in this variable.
The importance and implications of this finding are unknown at this time. Other
studies have shown that a significant change in weight in study subjects is also associated
with an improved outcome. In one study using a mouse model of human influenza
infection with secondary bacterial pneumonia, it was found that prophylactic treatment
(i.e. dosage begun 4 hours prior to viral infection) with oseltamivir resulted in an average
loss of only 5% of body weight in the mice, compared to an average of 25% loss in the
placebo mice.18 This study also showed that all mice in the prophylactic oseltamivir
group survived the viral and bacterial challenge, versus none of the mice in the placebo
group.
A second study was investigating the effect of early enteral nutrition (EEN) on
dogs with parvoviral enteritis.10 In this study, it was found that dogs in the EEN group
had a significant increase in weight gain from entry on all days of the study, while the
conventional group had no significant change in weight. In addition, dogs in the EEN
group showed a more rapid clinical improvement, based on normalization of clinical scores, than did the conventional group. While the difference was not significant, it was
also found that the 2 dogs that did not survive were both from the conventional group,
giving it a survival rate of 87% compared to 100% for the EEN group. These survival
statistics are very similar to those found in the present study. These results suggest that
the significant change in weight associated with oseltamivir use in this study could imply
that more significant beneficial effects on survival and/or disease recovery could also be
a plausible effect of the oseltamivir that was not brought out here.
The use of oseltamivir did not appear to be associated with any significant
adverse effects. The main side effects reported in humans are gastrointestinal effects
apparently due to direct local irritation of the gastric mucosa.15 In the experience of the
authors, dogs will also often react to the taste of the oseltamivir suspension and nausea
and vomiting can be encountered. Dilution with water just prior to administration
appears to minimize these effects. This practice was utilized in this study in an effort to
not only avoid uncovering group assignment and thereby instituting a bias, but also in an
effort to keep the clinical scores an accurate representation of the disease process in the
animal and not obscure these scores with drug reaction.
Analysis of the clinical scores, specifically vomiting and appetite, did not show
any difference between the treatment and control groups. This would tend to support the
lack of any significant adverse effects of oseltamivir administration versus placebo in this
patient population. The possibility that oseltamivir did have an effect to improve the
clinical effects of CPV enteritis in the treatment dogs, but itself caused increased
vomiting and nausea as a side effect of the drug and therefore concealed any benefit
evident by analysis of the clinical scores does exist. However, subjective observation was that administration of the oral medications (oseltamivir or placebo) was not
associated with initiating increased nausea or vomiting directly afterwards. This supports
the interpretation of results indicating that side effects of oseltamivir were minimal, as
were beneficial effects on decreasing disease morbidity.
The intensity of treatment required and the expected cost of treatment were
inferred based on additional therapy, such as colloid infusion or blood transfusions, as
well as prolonged hospitalization times, which were needed. Colloids were not
frequently used, in contrast to a previous report.26 Specifications for the institution of
colloid therapy were not elucidated in the previous study.
Protocol in this study required
significant decrease in total solids to 3.5g/dl. Much more modest decreases, often around
4.0 to 4.5g/dl, are frequently used in the clinic setting as indication for treatment with
colloids. A higher cutoff value as a trigger for colloid infusion likely would have
increased the incidence of its use in this study. Whether this increased use would
translate into a difference in usage between groups is unknown, but seems unlikely based
on the findings of a previous study showing no difference in albumin concentrations
between an EEN group and a conventional therapy group.10 Blood transfusions were also
rarely indicated. The 2 cases that did require a transfusion received fresh whole blood,
rather than packed red blood cells. Packed red blood cell availability was very limited at
the time of the first required transfusion. Fresh whole blood was collected from a donor
dog and administered in its place. In order to minimize differences in treatment between
dogs, when the second transfusion became necessary, although packed red blood cells
were available, fresh whole blood from the previous donor was again administered. The
total volume of crystalloids as well as colloids administered between the two groups may have been helpful to evaluate. Dogs experiencing greater fluid loss from vomiting and/or
diarrhea as well as having less voluntary intake per os would have a greater intravenous
fluid need. This would correlate with an increased severity of clinical signs and
manifestation of the disease process. Unfortunately, the collection of this data had
significant gaps or was outright missing from certain dogs due to recording error or
technical difficulties. Therefore this value was not analyzed.
The duration of clinical signs prior to presentation was not different between the
groups. It has been reported that for human influenza viral infections, oseltamivir is most
effective if started within the first 12 hours of clinical signs, with efficacy decreasing up
to 48 hours.24 For every 6 hour delay in starting oseltamivir, the duration of illness is
predicted to increase by approximately 8%.25 Whether this also holds true for its use in
CPV enteritis is unknown. Because replication of CPV does not depend on
neuraminidase, administration of oseltamivir in the early stages of infection is unlikely to
diminish viral replication and dissemination as with the influenza virus, and thus a timeefficacy
response is not expected. Rather, with the proposed mechanism against bacterial
translocation, oseltamivir may have a greater impact when administered during the period
of leukopenia and severe clinical signs. Further investigation is needed to expand on
these speculations.
The treatment group may have been further along in their course of disease,
despite the lack of difference in reported duration of clinical signs. This would be
supported by the fact that this group, on average, had a slightly lower white blood cell
and neutrophil counts at entry, as well as a somewhat quicker rebound after these
numbers dropped. The clinical scores also showed the trend of quicker improvements in the treatment group. With the inherent inaccuracies of estimation of duration of clinical
signs by the owner or caretaker, it is plausible that the times reported at entry were not
correct, and that the treatment group did include dogs at a more advanced stage of
disease. Conversely, if the reported duration of signs was accurate, the seemingly
quicker recovery of the treatment dogs could be attributed to a beneficial effect of
oseltamivir.
A clinical scoring system was utilized in order to evaluate the subjective criteria
of attitude and appetite, as well as to quantify the severity of vomiting and characterize
the feces to allow for comparison across dogs. One investigator (MRS) had the
responsibility of assigning scores to all dogs to minimize inter-observer variability. This
investigator was also blinded to group assignment in order to minimize bias.
Values for each category and cumulative scores were compared between the 2 groups for
each day, and although mild trends could be seen for lower scores in the treatment group,
there were no significant differences. This could be attributed to the small sample size in
this study, as well as the variability in the timeline of illness among dogs. Since dogs
presented in all stages of their disease (i.e. clinical symptoms for less than 12 hours to up
to 4 days), a straight out comparison of scores per day may not illustrate true differences
and a larger group would be needed to further examine this effect. In addition, the
clinical scoring system utilized is a very simple system, and as such, was relatively
insensitive in its ability to differentiate between various stages of aberrancy in each of the
clinical attributes. There was not much room to allow for representation of subtle yet
clinically significant differences. A scoring system with a greater degree of stratification between assigned values may allow for a greater sensitivity and a more accurate
representation of the clinical status of the patient.
CPV is not reliant on neuraminidase for replication. However, anecdotal reports
of the use of oseltamivir in dogs with CPV enteritis have claimed decreased morbidity
and shortened recovery time in the treated dogs. It is speculated that the drug may inhibit
bacterial translocation that subsequently leads to endotoxemia, sepsis, SIRS and death.
Bacterial adherence and colonization of respiratory epithelial cells is potentiated in the
presence of viral NA, and inhibited with NA blocking agents.17-19 It is believed that the
bacteria that commonly invade the lower respiratory tract express their own NA, thus
enabling them to penetrate the protective mucin layer and infect the epithelial cells.17
Although unproven, a similar mechanism may exist in the gastrointestinal tract.
Oseltamivir may exert a beneficial effect by inhibiting NA on enteric bacteria, preventing
their translocation across the gastrointestinal mucosal barrier. In CPV enteritis, the
mucosal barrier is already impaired, allowing easier passage of bacteria. If bacterial NA
plays a role similar to that in the lungs, the NA would cleave sialic acid residues on the
gut epithelium, exposing receptor sites for bacterial adherence and further encouraging
translocation. In addition, CPV suppresses the dogís immune system, both humoral and
cell-mediated factors, allowing for systemic spread of bacteria and the resultant
deleterious effects. Further studies are needed to accurately define the actual mechanism
behind the observed anecdotal benefits of the use of oseltamivir to treat CPV enteritis.
Limitations
Limitations of this study do involve the concern of administration of an oral
medication to a vomiting patient, and its variable systemic absorption in the face of a diseased gastrointestinal tract. Gastric emptying times are quicker for liquid substances
as compared to solids, with gastric emptying starting as soon as 10-30 minutes after
administration. The oseltamivir suspension thus has the probability of starting to move
through the gastrointestinal system and being absorbed before an episode of vomiting
occurs. In addition, the act of vomiting is reported to only empty 40-50% of stomach
contents. This would suggest that even with the presence of vomiting, it is reasonable to
expect that at least a portion of the drug will remain in the system. Early safety studies of
oseltamivir show that it has a bioavailability of 73% in healthy dogs, with detectable
levels of the drug in plasma within approximately 30 minutes after oral administration.27
Oseltamivir does require transformation to its active metabolite by esterases located
within the liver, and to a certain degree, within the intestinal system. 27, 28 The
importance of the intestinal system esterases is unknown. Due to this need for
transformation, it is believed that oseltamivir effects are not due to a purely local action,
but do require systemic distribution. The effect of a diseased gastrointestinal system such
as that seen in CPV enteritis on the absorption, systemic distribution and transformation
is unknown at this time and future pharmacokinetic studies, in this situation especially,
are needed.
The reasoning behind any beneficial effect of oseltamivir in the treatment of CPV
enteritis suggests that it helps decrease bacterial translocation and therefore the ensuing
endotoxemia, SIRS and MODS that can develop. In this study, although certain physical
and clinic pathologic parameters were monitored, there was no direct test for the presence
of bacterial translocation or sepsis. SIRS criteria were evaluated, but this is a fairly crude
assessment, especially considering the confounding factors. As the dogs were starting to feel better, they would oftentimes become very excitable when being handled. This
frequently resulted in an elevation of their heart rate to over 140 bpm, or their respiratory
rate to greater than 40/min. The presence of these two variables would classify these
healthy, excitable puppies as being positive for SIRS. In addition, the effect of the virus
itself on the white blood cell count confounds the definition slightly. A WBC of less than
6,000 cells/ul can simply reflect destruction of progenitor cells in the bone marrow and is
not necessarily associated with systemic inflammation. Other methods to evaluate for the
presence of bacterial translocation, endotoxemia or SIRS would be more fruitful. Culture
of mesenteric lymph nodes is considered the gold standard in human medicine and
animal models for evaluation of bacterial translocation.29 The feasibility of this
procedure in this patient population (client-owned, live animals) and setting is
questionable. Other methods, such as blood cultures or measurement of serum endotoxin
levels or other inflammatory mediators may provide a more accessible method for
differentiating animals in which bacterial translocation is present from those in which it is
not. Further investigation would be needed before any true conclusions can be made.
CONCLUSIONS
CPV enteritis can be a devastating disease process. The financial constraints
often encountered with treatment can be very frustrating given the treatable nature of this
disease. Despite the anecdotal reports touting the success of oseltamivir to decrease the
disease morbidity and mortality of CPV enteritis, scientific evidence of this was not
found in this study. However, a significant difference in the change in body weight
during hospitalization stay was established, as was the apparent safety of the drug in this
31
patient population. It is believed that, given the paucity of adverse side effeccts and the
findings presented in this study, further investigation is warranted not only for its effects
in CPV enteritis, but possibly any disease state in which bacterial translocation is a
concern.
REFERENCES:
1. Hoskins JD. Canine viral enteritis, in Greene CE, 2nd Ed (ed): Infectious disease
of the dog and cat. Philadelphia, WB Saunders, 1998, pp40-44.
2. Otto CM, Jackson CB, Rogell EJ, et al. Recombinant bactericidal/permeabilityincreasing
protein for treatment of parvovirus enteritis: a randomized, doubleblinded,
placebo-controlled trial. J Vet Intern Med 2001; 15:355-360.
3. Kariuki Njenga M, Nyaga PN, Buoro IBJ, Gathumbi PK. Effectiveness of fluids
and antibiotics as supportive therapy of canine parvovirus-2 enteritis in puppies.
Bull Anim Health Pod Afr 1990; 38:379-389.
4. Glickman LT, Domanski LM, Patronek GJ, et al. Breed-related risk factors for
canine parvovirus enteritis. J Am Vet Med Assoc 1985; 187:589-594.
5. Macintire DK, Smith-Carr S. Canine parvovirus part II. Clinical signs, diagnosis,
and treatment. Comp Cont Ed Pract Vet 1997; 19(3):291-302.
6. Otto CM, Drobatz KJ, Soter C. Endotoxemia and tumor necrosis factor activity in
dogs with naturally occurring parvoviral enteritis. J Vet Intern Med 1997; 11:65-
70.
7. Mann FA, Boon GD, Wagner-Mann CC, et al. Ionized and total magnesium
concentrations in blood from dogs with naturally acquired parvoviral enteritis. J
Am Vet Med Assoc 1998; 212:1398-1401. 8. Rewerts JM, McCaw DL, Cohn LA, et al. Recombinant human granulocyte
colony-stimulating factor for treatment of puppies with neutropenia secondary to
canine parvovirus infection. J Am Vet Med Assoc 1998; 213:991-992.
9. Mischke R, Barth T, Wohlsein P, et al. Effect of recombinant human granulocyte
colony-stimulating factor on leukocyte count and survival rate of dogs with
parvoviral enteritis. Res Vet Sci 2001; 70:221-225.
10. Mohr AJ, Leisewitz AL, Jacobson LS, et al. Effect of early enteral nutrition on
intestinal permeability, intestinal protein loss, and outcome in dogs with severe
parvoviral enteritis. J Vet Intern Med 2003; 17:791-798.
11. Cohn LA, Rewerts JM, McCaw D, et al. Plasma granulocyte colony stimulating
factor concentrations in neutropenic, parvoviral enteritis-infected puppies. J Vet
Intern Med 1999; 13:581-586.
12. Dimmitt R. Clinical experience with cross-protective antiendotoxin antiserum in
dogs with parvoviral enteritis. Canine Pract 1991; 16:23-26.
13. De Mari K, Maynard L, Eun HM, et al. Treatment of canine parvoviral enteritis
with interferon-omega in a placebo-controlled field trial. Vet Rec 2003; 152:105-
108.
14. Martin V, Najbar W, Gueguen S, et al. Treatment of canine parvoviral enteritis
with interferon-omega in a placebo-controlled challenge trial. Vet Micro 2002;
89:115-127.
15. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors.
Lancet 2000; 335:827-835. 16. Kaiser L, Wat C, Mills T, Mahoney R, Ward P, Hayden F. Impact of oseltamivir
treatment on influenza-related lower respiratory tract complications and
hospitalizations. Arch Intern Med 2003; 163:1667-1672.
17. McCuller JA, Bartmess KC. Role of neuraminidase in lethal synergism between
influenza virus and Streptococcus pneumoniae. J Infect Dis 2003; 187:1000-
1009.
18. McCullers JA. Effect of antiviral treatment on the outcome of secondary bacterial
pneumonia after influenza. J Infect Dis 2004; 190:519-526.
19. Peltola VT, Murti KG, McCullers JA. Influenza virus neuraminidase contributes
to secondary bacterial pneumonia. J Infect Dis 2005; 192:249-257.
20. Bhatia A, Kast RE. How influenzaís neuraminidase promotes virulence and
creates localized lung mucosa immunodeficiency. Cell & Mole Bio Letters 2007;
12:111-119.
21. Matheson NJ, Harden AR, Perera R, Sheikh A, Symmonds-Abrahams M.
Neuraminidase inhibitors for preventing and treating influenza in children
(review). Cochrane Lib 2007; 1:1-40.
22. Turk J, Miller M, Brown T, er al. Coliform septicemia and pulmonary disease
associated with canine parvoviral enteritis: 88 cases (1987-1988). J Am Vet Med
Assoc 1990; 196:771-773.
23. Smith-Carr S, Macintire DK, Swango LJ. Canine parvovirus part I. Pathogenesis
and vaccination. Comp Cont Ed Pract Vet 1997; 19(2):125-132.
36
24. Houston DM, Ribble CS, Head LL. Risk factors associated wiith parvovirus
enteritis in dogs: 283 cases (1982-1991). J Am Vet Med Assoc 1996; 208:542-
546.
25. Gillissen A, Hoffken G. Early therapy with the neuraminidase inhibitor
oseltamivir maximizes its efficacy in influenza treatment. Med Microbiol
Immunol 2002; 191:165-168.
26. Mantione NL, Otto CM. Characterization of the use of antiemetic agents in dogs
with parvoviral enteritis treated at a veterinary teaching hospital: 77 cases (1997-
2000). J Am Vet Med Assoc 2005; 227:1787-1793.
27. Li W, Escarpe PA, Eisenberg EJ, Cundy KC, Sweet C, et al. Identification of GS
4104 as an orally bioabailable prodrug of the influenza virus neuraminidase
inhibitor GS 4071. Antimicrob Agents Chemother 1998; 42:647-653.
28. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug
oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999;
37:471-484.
29. Gatt M, Reddy BS, Macfie J. Review article: bacterial translocation in the
critically ill ñ evidence and methods of prevention. Aliment Pharmacol Ther
2007; 25:741-757.
No hay comentarios:
Publicar un comentario