Gamma/Delta T lymphocytes are a unique T cell population with
important anti-inflammatory capabil... more Gamma/Delta T lymphocytes are a unique T cell population with important anti-inflammatory capabilities. Their role in acute lung injury, however, is poorly understood but may provide significant insight into lung-protective mechanisms occurring after injury. In a murine model of lung injury, wild-type C57BL/6 and TCRd2/2 mice were exposed to Escherichia coli LPS, followed by analysis of gd T cell and macrophage subsets. In the absence of gd T cells, TCRd2/2 mice developed increased inflammation and alveolar-capillary leak compared with wild-type C57BL/6 mice after LPS exposure that correlated with expansion of distinct macrophage populations. Classically activated M1 macrophages were increased in the lung of TCRd2/2 mice at d 1, 4, and 7 after LPS exposure that peaked at d 4 and persisted at d 7 compared with wild-type animals. In response to LPS, Vg1 and Vg7 gd T cells were expanded in the lung and expressed IL-4. Coculture experiments showed decreased expression of TNF-a by resident alveolar macrophages in the presence of gd T cells that was reversed in the presence of an anti-IL-4-blocking antibody. Treatment of mice with rIL4 resulted in reduced numbers of M1 macrophages, inflammation, and alveolar-capillary leak. Therefore, one mechanism by which Vg1 and Vg7 gd T cells protect against LPS-induced lung injury is through IL-4 expression, which decreases TNF-a production by resident alveolar macrophages, thus reducing accumulation of M1 macrophages, inflammation, and alveolar-capillary leak. J. Leukoc. Biol. 99: 373–386; 2016.
Objectives: To evaluate dexmedetomidine as adjunctive therapy to
lorazepam for severe alcohol wit... more Objectives: To evaluate dexmedetomidine as adjunctive therapy to lorazepam for severe alcohol withdrawal. Design: Prospective, randomized, double-blind, placebo-controlled trial. Setting: Single center; medical ICU. Patients: Twenty-four adult patients with a Clinical Institute Withdrawal Assessment score greater than or equal to 15 despite greater than or equal to 16 mg of lorazepam over a 4-hour period. Interventions: Patients received a symptom-triggered Clinical Institute Withdrawal Assessment protocol with lorazepam and were randomized to dexmedetomidine 1.2 μg/kg/hr (high dose), 0.4 μg/kg/hr (low dose), or placebo as adjunctive therapy for up to 5 days or resolution of withdrawal symptoms. Measurement and Main Results: High-dose and low-dose groups were combined as a single dexmedetomidine group for primary analysis with secondary analysis exploring a dose-response relationship. The difference in 24-hour lorazepam requirements after versus before study drug was greater in the dexmedetomidine group compared with the placebo group (–56 mg vs –8 mg, p = 0.037). Median differences were similar for high dose and low dose. The 7-day cumulative lorazepam requirements were not statistically different between dexmedetomidine and placebo (159 mg vs 181 mg). Clinical Institute Withdrawal Assessment or Riker sedation-agitation scale scores representing severe agitation (13% vs 25%) or moderate agitation (27% vs 22%) within 24 hours of initiating study drug were similar for dexmedetomidine and placebo groups, respectively. Bradycardia occurred more frequently in the dexmedetomidine group versus placebo group (25% vs 0%, p = not significant), with the majority of bradycardia occurring in the high-dose group (37.5%). Study drug rate adjustments occurred more often in the dexmedetomidine group compared with the placebo group (50% vs 0%, p = 0.02). Neither endotracheal intubation nor seizure occurred in any group while on study drug. Conclusions: Adjunctive dexmedetomidine for severe alcohol withdrawal maintains symptom control and reduces lorazepam exposure in the short term, but not long term, when using a symptom- triggered protocol. Monitoring for bradycardia is needed with dexmedetomidine but the occurrence may be lessened with low dose. Further study is needed to evaluate the clinical impact of dexmedetomidine. (Crit Care Med 2014; 42:1131–1139) Key Words: alcohol withdrawal; benzodiazepine; critical care; dexmedetomidine; intensive care
Gamma/Delta T lymphocytes are a unique T cell population with
important anti-inflammatory capabil... more Gamma/Delta T lymphocytes are a unique T cell population with important anti-inflammatory capabilities. Their role in acute lung injury, however, is poorly understood but may provide significant insight into lung-protective mechanisms occurring after injury. In a murine model of lung injury, wild-type C57BL/6 and TCRd2/2 mice were exposed to Escherichia coli LPS, followed by analysis of gd T cell and macrophage subsets. In the absence of gd T cells, TCRd2/2 mice developed increased inflammation and alveolar-capillary leak compared with wild-type C57BL/6 mice after LPS exposure that correlated with expansion of distinct macrophage populations. Classically activated M1 macrophages were increased in the lung of TCRd2/2 mice at d 1, 4, and 7 after LPS exposure that peaked at d 4 and persisted at d 7 compared with wild-type animals. In response to LPS, Vg1 and Vg7 gd T cells were expanded in the lung and expressed IL-4. Coculture experiments showed decreased expression of TNF-a by resident alveolar macrophages in the presence of gd T cells that was reversed in the presence of an anti-IL-4-blocking antibody. Treatment of mice with rIL4 resulted in reduced numbers of M1 macrophages, inflammation, and alveolar-capillary leak. Therefore, one mechanism by which Vg1 and Vg7 gd T cells protect against LPS-induced lung injury is through IL-4 expression, which decreases TNF-a production by resident alveolar macrophages, thus reducing accumulation of M1 macrophages, inflammation, and alveolar-capillary leak. J. Leukoc. Biol. 99: 373–386; 2016.
Objectives: To evaluate dexmedetomidine as adjunctive therapy to
lorazepam for severe alcohol wit... more Objectives: To evaluate dexmedetomidine as adjunctive therapy to lorazepam for severe alcohol withdrawal. Design: Prospective, randomized, double-blind, placebo-controlled trial. Setting: Single center; medical ICU. Patients: Twenty-four adult patients with a Clinical Institute Withdrawal Assessment score greater than or equal to 15 despite greater than or equal to 16 mg of lorazepam over a 4-hour period. Interventions: Patients received a symptom-triggered Clinical Institute Withdrawal Assessment protocol with lorazepam and were randomized to dexmedetomidine 1.2 μg/kg/hr (high dose), 0.4 μg/kg/hr (low dose), or placebo as adjunctive therapy for up to 5 days or resolution of withdrawal symptoms. Measurement and Main Results: High-dose and low-dose groups were combined as a single dexmedetomidine group for primary analysis with secondary analysis exploring a dose-response relationship. The difference in 24-hour lorazepam requirements after versus before study drug was greater in the dexmedetomidine group compared with the placebo group (–56 mg vs –8 mg, p = 0.037). Median differences were similar for high dose and low dose. The 7-day cumulative lorazepam requirements were not statistically different between dexmedetomidine and placebo (159 mg vs 181 mg). Clinical Institute Withdrawal Assessment or Riker sedation-agitation scale scores representing severe agitation (13% vs 25%) or moderate agitation (27% vs 22%) within 24 hours of initiating study drug were similar for dexmedetomidine and placebo groups, respectively. Bradycardia occurred more frequently in the dexmedetomidine group versus placebo group (25% vs 0%, p = not significant), with the majority of bradycardia occurring in the high-dose group (37.5%). Study drug rate adjustments occurred more often in the dexmedetomidine group compared with the placebo group (50% vs 0%, p = 0.02). Neither endotracheal intubation nor seizure occurred in any group while on study drug. Conclusions: Adjunctive dexmedetomidine for severe alcohol withdrawal maintains symptom control and reduces lorazepam exposure in the short term, but not long term, when using a symptom- triggered protocol. Monitoring for bradycardia is needed with dexmedetomidine but the occurrence may be lessened with low dose. Further study is needed to evaluate the clinical impact of dexmedetomidine. (Crit Care Med 2014; 42:1131–1139) Key Words: alcohol withdrawal; benzodiazepine; critical care; dexmedetomidine; intensive care
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Papers by Jim Lavelle
important anti-inflammatory capabilities. Their role in
acute lung injury, however, is poorly understood but may
provide significant insight into lung-protective mechanisms
occurring after injury. In a murine model of lung
injury, wild-type C57BL/6 and TCRd2/2 mice were exposed
to Escherichia coli LPS, followed by analysis of gd
T cell and macrophage subsets. In the absence of gd
T cells, TCRd2/2 mice developed increased inflammation
and alveolar-capillary leak compared with wild-type
C57BL/6 mice after LPS exposure that correlated with
expansion of distinct macrophage populations. Classically
activated M1 macrophages were increased in the
lung of TCRd2/2 mice at d 1, 4, and 7 after LPS exposure
that peaked at d 4 and persisted at d 7 compared with
wild-type animals. In response to LPS, Vg1 and Vg7 gd
T cells were expanded in the lung and expressed IL-4.
Coculture experiments showed decreased expression
of TNF-a by resident alveolar macrophages in the
presence of gd T cells that was reversed in the presence
of an anti-IL-4-blocking antibody. Treatment of mice with
rIL4 resulted in reduced numbers of M1 macrophages,
inflammation, and alveolar-capillary leak. Therefore, one
mechanism by which Vg1 and Vg7 gd T cells protect
against LPS-induced lung injury is through IL-4 expression,
which decreases TNF-a production by resident
alveolar macrophages, thus reducing accumulation of
M1 macrophages, inflammation, and alveolar-capillary
leak. J. Leukoc. Biol. 99: 373–386; 2016.
lorazepam for severe alcohol withdrawal.
Design: Prospective, randomized, double-blind, placebo-controlled
trial.
Setting: Single center; medical ICU.
Patients: Twenty-four adult patients with a Clinical Institute Withdrawal
Assessment score greater than or equal to 15 despite
greater than or equal to 16 mg of lorazepam over a 4-hour period.
Interventions: Patients received a symptom-triggered Clinical
Institute Withdrawal Assessment protocol with lorazepam and
were randomized to dexmedetomidine 1.2 μg/kg/hr (high dose),
0.4 μg/kg/hr (low dose), or placebo as adjunctive therapy for up
to 5 days or resolution of withdrawal symptoms.
Measurement and Main Results: High-dose and low-dose groups
were combined as a single dexmedetomidine group for primary
analysis with secondary analysis exploring a dose-response relationship.
The difference in 24-hour lorazepam requirements after
versus before study drug was greater in the dexmedetomidine
group compared with the placebo group (–56 mg vs –8 mg,
p = 0.037). Median differences were similar for high dose and low
dose. The 7-day cumulative lorazepam requirements were not statistically
different between dexmedetomidine and placebo (159 mg
vs 181 mg). Clinical Institute Withdrawal Assessment or Riker
sedation-agitation scale scores representing severe agitation (13%
vs 25%) or moderate agitation (27% vs 22%) within 24 hours of
initiating study drug were similar for dexmedetomidine and placebo
groups, respectively. Bradycardia occurred more frequently
in the dexmedetomidine group versus placebo group (25% vs 0%,
p = not significant), with the majority of bradycardia occurring in the
high-dose group (37.5%). Study drug rate adjustments occurred
more often in the dexmedetomidine group compared with the placebo
group (50% vs 0%, p = 0.02). Neither endotracheal intubation
nor seizure occurred in any group while on study drug.
Conclusions: Adjunctive dexmedetomidine for severe alcohol
withdrawal maintains symptom control and reduces lorazepam
exposure in the short term, but not long term, when using a symptom-
triggered protocol. Monitoring for bradycardia is needed with
dexmedetomidine but the occurrence may be lessened with low
dose. Further study is needed to evaluate the clinical impact of
dexmedetomidine. (Crit Care Med 2014; 42:1131–1139)
Key Words: alcohol withdrawal; benzodiazepine; critical care;
dexmedetomidine; intensive care
important anti-inflammatory capabilities. Their role in
acute lung injury, however, is poorly understood but may
provide significant insight into lung-protective mechanisms
occurring after injury. In a murine model of lung
injury, wild-type C57BL/6 and TCRd2/2 mice were exposed
to Escherichia coli LPS, followed by analysis of gd
T cell and macrophage subsets. In the absence of gd
T cells, TCRd2/2 mice developed increased inflammation
and alveolar-capillary leak compared with wild-type
C57BL/6 mice after LPS exposure that correlated with
expansion of distinct macrophage populations. Classically
activated M1 macrophages were increased in the
lung of TCRd2/2 mice at d 1, 4, and 7 after LPS exposure
that peaked at d 4 and persisted at d 7 compared with
wild-type animals. In response to LPS, Vg1 and Vg7 gd
T cells were expanded in the lung and expressed IL-4.
Coculture experiments showed decreased expression
of TNF-a by resident alveolar macrophages in the
presence of gd T cells that was reversed in the presence
of an anti-IL-4-blocking antibody. Treatment of mice with
rIL4 resulted in reduced numbers of M1 macrophages,
inflammation, and alveolar-capillary leak. Therefore, one
mechanism by which Vg1 and Vg7 gd T cells protect
against LPS-induced lung injury is through IL-4 expression,
which decreases TNF-a production by resident
alveolar macrophages, thus reducing accumulation of
M1 macrophages, inflammation, and alveolar-capillary
leak. J. Leukoc. Biol. 99: 373–386; 2016.
lorazepam for severe alcohol withdrawal.
Design: Prospective, randomized, double-blind, placebo-controlled
trial.
Setting: Single center; medical ICU.
Patients: Twenty-four adult patients with a Clinical Institute Withdrawal
Assessment score greater than or equal to 15 despite
greater than or equal to 16 mg of lorazepam over a 4-hour period.
Interventions: Patients received a symptom-triggered Clinical
Institute Withdrawal Assessment protocol with lorazepam and
were randomized to dexmedetomidine 1.2 μg/kg/hr (high dose),
0.4 μg/kg/hr (low dose), or placebo as adjunctive therapy for up
to 5 days or resolution of withdrawal symptoms.
Measurement and Main Results: High-dose and low-dose groups
were combined as a single dexmedetomidine group for primary
analysis with secondary analysis exploring a dose-response relationship.
The difference in 24-hour lorazepam requirements after
versus before study drug was greater in the dexmedetomidine
group compared with the placebo group (–56 mg vs –8 mg,
p = 0.037). Median differences were similar for high dose and low
dose. The 7-day cumulative lorazepam requirements were not statistically
different between dexmedetomidine and placebo (159 mg
vs 181 mg). Clinical Institute Withdrawal Assessment or Riker
sedation-agitation scale scores representing severe agitation (13%
vs 25%) or moderate agitation (27% vs 22%) within 24 hours of
initiating study drug were similar for dexmedetomidine and placebo
groups, respectively. Bradycardia occurred more frequently
in the dexmedetomidine group versus placebo group (25% vs 0%,
p = not significant), with the majority of bradycardia occurring in the
high-dose group (37.5%). Study drug rate adjustments occurred
more often in the dexmedetomidine group compared with the placebo
group (50% vs 0%, p = 0.02). Neither endotracheal intubation
nor seizure occurred in any group while on study drug.
Conclusions: Adjunctive dexmedetomidine for severe alcohol
withdrawal maintains symptom control and reduces lorazepam
exposure in the short term, but not long term, when using a symptom-
triggered protocol. Monitoring for bradycardia is needed with
dexmedetomidine but the occurrence may be lessened with low
dose. Further study is needed to evaluate the clinical impact of
dexmedetomidine. (Crit Care Med 2014; 42:1131–1139)
Key Words: alcohol withdrawal; benzodiazepine; critical care;
dexmedetomidine; intensive care