Download The initial management of acetaminophen poisoning is determined

The initial management of acetaminophen poisoning is determined by the patient's presenting
symptoms. Most patients who present early (within 24 hours) after an acute acetaminophen
ingestion are asymptomatic, while others may require treatment for symptoms related to
coingestants.
As there are no early symptoms that predict acetaminophen toxicity, poisoning severity
following an acute ingestion is quantified by plotting a timed serum acetaminophen
concentration on the modified Rumack-Matthew nomogram (figure 1). Use of the nomogram, as
well as risk factors for hepatotoxicity and the diagnosis of both acute and chronic
acetaminophen poisoning, are discussed separately. A summary table to facilitate emergent
management is provided
Patients who present later may manifest symptoms and signs of hepatic injury or failure, such
as nausea, vomiting, jaundice, abdominal pain, renal injury, coagulopathy (eg, gastrointestinal
bleeding), hepatic encephalopathy, cerebral edema, or hypotension. These patients may
require emergent resuscitation, including airway management, intravenous fluids, vasopressors,
hemodialysis, or management of cerebral edema.
GASTROINTESTINAL DECONTAMINATION — Adult patients who present soon after a
potentially toxic ingestion of acetaminophen (single dose ≥7.5 g) are likely to benefit from
gastrointestinal (GI) decontamination. We suggest treatment with activated charcoal (AC),
1 g/kg (maximum dose 50 g) by mouth in all patients who present within four hours of a known
or suspected acetaminophen ingestion, unless there are contraindications to its administration.
Charcoal should be withheld in patients who are sedated and may not be able to protect their
airway, unless endotracheal intubation is performed first. However, endotracheal intubation
should not be performed solely for the purpose of giving charcoal. Asymptomatic patients who
present more than four hours after a reported ingestion are unlikely to benefit from AC, and we
do not recommend routine treatment in these patients. A general approach to decontamination
of poisoned patients is discussed separately.
A comparison of the efficacy of gastric lavage, ipecacuanha and activated charcoal in the emergency management of paracetamol
overdose.
AU
Underhill TJ, Greene MK, Dove AF
SO
Arch Emerg Med. 1990;7(3):148.
The aim of this prospective trial was to compare the efficacy of gastric lavage, activated charcoal and ipecacuanha at limiting the
absorption of paracetamol in overdose and to assess the significance of the continued absorption of paracetamol following treatment.
Patients aged 16 and over who had ingested 5 gms or more of paracetamol within 4h of admission were entered into the trial. The
percentage fall in plasma paracetamol level was used as the measure of the success of a treatment at limiting absorption. The mean
percentage fall was 39.3 for gastric lavage, 52.2 for activated charcoal and 40.7 for ipecacuanha, with a significant difference between
the treatment methods (p = 0.03). Activated charcoal was more effective at limiting the absorption of paracetamol following overdose than
either gastric lavage or ipecacuanha induced emesis. In treated patients continuing paracetamol absorption is not significant if more than
2h have elapsed since ingestion.
A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose.
AU
Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ
SO
Ann Emerg Med. 1994;23(3):519.
STUDY OBJECTIVE: To evaluate whether activated charcoal (AC) reduces the efficacy of subsequent oral N-acetylcysteine therapy
during acute acetaminophen overdose.
DESIGN: Prospective observational case series of all acute acetaminophen overdoses reported to three certified regional poison centers.
TYPES OF PATIENTS: All patients with acute acetaminophen overdose in whom N-acetylcysteine therapy was initiated within 16 hours
after ingestion.
INTERVENTIONS: All patients were treated with oral N-acetylcysteine therapy for 72 hours. The decision to use AC was left to the
treating physician without input from the investigator.
MEASUREMENTS AND RESULTS: One hundred twenty-two patients were evaluated. Maximum recorded SGOT levels of more than
125 U/mL were defined as evidence of hepatotoxicity. AC was used in addition to N-acetylcysteine in 82 of 122 patients. Hepatotoxicity
developed in four of 82 patients who received AC versus ten of 40 patients who did not receive AC (P<.005). An increasing dose of Nacetylcysteine provided no additional benefit (P>.05). Spacing the administration of AC and oral N-acetylcysteine less than or more than
two hours apart did not affect outcome (P>.05).
CONCLUSION: Administration of AC before the administration of oral N-acetylcysteine in acetaminophen overdose does not reduce the
efficacy of N-acetylcysteine therapy and may provide some additional hepatoprotective benefit. The practice of increasing the dose of
oral N-acetylcysteine therapy after the administration of AC appears unwarranted.
Efficacy of activated charcoal administered more than four hours after acetaminophen overdose.
AU
Spiller HA, Winter ML, Klein-Schwartz W, Bangh SA
SO
J Emerg Med. 2006;30(1):1.
To evaluate whether administration of activated charcoal, in addition to standard N-acetylcysteine (NAC) therapy, after acetaminophen
overdose provides additional patient benefit over NAC therapy alone, a 1-year non-randomized prospective, multi-center, observational
case series was performed at three poison centers and one poison center system. Entrance criteria were all acute acetaminophen
overdoses with: 1) an acetaminophen blood concentration determined to be in the toxic range by the Rumack-Matthew nomogram; and
2) all therapies, including NAC and activated charcoal, initiated between 4 and 16 h post-ingestion. There were 145 patients meeting
entrance criteria, of whom 58 patients (40%) received NAC only and 87 patients (60%) received NAC and activated charcoal. Overall, 23
patients had elevations of AST or ALT greater than 1000 IU/L, of which 21 patients received NAC only (38% of total NAC only group) and
2 patients received NAC and activated charcoal (2% of total NAC+AC group). Administration of activated charcoal in this series of
patients with toxic acetaminophen concentrations treated with NAC was associated with reduced incidence of liver injury, as measured
by elevated serum transaminases and prothrombin times.
ANTIDOTE: ACETYLCYSTEINE
Effectiveness of acetylcysteine — N-acetylcysteine is the accepted antidote
for acetaminophen poisoning and is given to all patients at significant risk for hepatotoxicity.
Serious hepatotoxicity is uncommon and death extremely rare if N-acetylcysteine is
administered within eight hours following acetaminophen overdose [10-12].
The key to effective treatment is to start therapy before the onset of liver injury, which can be
defined biochemically by an elevation of the alanine aminotransferase (ALT). This is
accomplished by initiating treatment within eight hours of an acute ingestion. Determination of
the risk for hepatotoxicity following either acute or chronic acetaminophen ingestion is
discussed separately
Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol.
AU
Smilkstein MJ, Bronstein AC, Linden C, Augenstein WL, Kulig KW, Rumack BH
SO
Ann Emerg Med. 1991;20(10):1058.
STUDY OBJECTIVE: To determine the safety and efficacy of a 48-hour IV N-acetylcysteine (IV NAC) treatment protocol for acute
acetaminophen overdose.
DESIGN: Nonrandomized trial open to all eligible patients.
SETTING: Multicenter; hospitals included moderate- and high-volume private, university, and municipal hospitals in urban and suburban
settings.
TYPE OF PARTICIPANTS: Two hundred twenty-three patients were entered. Of these, 179 met inclusion criteria: acute acetaminophen
overdose, plasma acetaminophen concentration above the treatment nomogram line, treatment with IV NAC according to the protocol,
and sufficient data to determine outcome.
INTERVENTIONS: IV NAC treatment consisted of a loading dose of 140 mg/kg followed by 12 doses of 70 mg/kg every four hours.
MEASUREMENTS AND MAIN RESULTS: Patients were grouped for analysis according to risk group based on the initial plasma
acetaminophen concentration. Hepatotoxicity (aspartate aminotransferase or alanine aminotransferase of more than 1,000 IU/L)
developed in 10% (five of 50) of patients at "probable risk" when IV NAC was started within ten hours of acetaminophen ingestion and in
27.1% (23 of 85) when therapy was begun after ten to 24 hours. Among "high-risk" patients first treated 16 to 24 hours after overdose,
hepatotoxicity occurred in 57.9% (11 of 19). There were two deaths (two of 179, 1.1%). Adverse reactions resulting from NAC occurred in
32 of 223 cases (14.3%), consisting in 29 of 32 patients (91% of reactions) of transient, patchy, skin erythema or mild urticaria during the
loading dose that did not require discontinuation of therapy.
CONCLUSION: This 48-hour IV NAC protocol is safe and effective antidotal therapy for acetaminophen overdose. Based on available
data, it is equal to 72-hour oral and 20-hour IV treatment protocols when started early and superior to the 20-hour IV regimen when
treatment is delayed. Further study will be required to determine its relative efficacy in the high-risk patient treated very late.
Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985)
AU
Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH
SO
N Engl J Med. 1988;319(24):1557.
During the investigational use of oral N-acetylcysteine as an antidote for poisoning with acetaminophen, 11,195 cases of suspected
acetaminophen overdose were reported. We describe the outcomes of 2540 patients with acetaminophen ingestions treated with a
loading dose of 140 mg of oral N-acetylcysteine per kilogram of body weight, followed four hours later by 70 mg per kilogram given every
four hours for an additional 17 doses. Patients were categorized for analysis on the basis of initial plasma acetaminophen concentrations
and the interval between ingestion and treatment. Hepatotoxicity developed in 6.1 percent of patients at probable risk when Nacetylcysteine was started within 10 hours of acetaminophen ingestion and in 26.4 percent of such patients when therapy was begun 10
to 24 hours after ingestion. Among patients at high risk who were treated 16 to 24 hours after an acetaminophen overdose, hepatotoxicity
developed in 41 percent--a rate lower than that among historical controls. When given within eight hours of acetaminophen ingestion, Nacetylcysteine was protective regardless of the initial plasma acetaminophen concentration. There was no difference in outcome whether
N-acetylcysteine was started zero to four or four to eight hours after ingestion, but efficacy decreased with further delay. There were 11
deaths among the 2540 patients (0.43 percent); in the nine fatal cases in which aminotransferase was measured before treatment,
values were elevated before N-acetylcysteine was started. No deaths were clearly caused by acetaminophen among patients in whom Nacetylcysteine therapy was begun within 16 hours. We conclude that N-acetylcysteine treatment should be started within eight hours of
an acetaminophen overdose, but that treatment is still indicated at least as late as 24 hours after ingestion. On the basis of available
data, the 72-hour regimen of oral N-acetylcysteine is as effective as the 20-hour intravenous regimen described previously, and it may be
superior when treatment is delayed.
Some debate continues about the appropriate route and duration of early Nacetylcysteine therapy following acute ingestion. The two most common protocols are the 20
hour intravenous (IV) protocol [15] and the 72 hour oral protocol [11]. We review these protocols
immediately below. A discussion of how they are modified based upon clinical circumstances is
discussed further on.
Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine.
AU
Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT
SO
Lancet. 1977;2(8035):432.
Fifteen patients with paracetamol (acetaminophen) poisoning were treated with intravenous N-acetylcystein (300 mg/kg given over 20 h).
Mean admission and 4 h plasma-paracetamol concentrations were 262 and 369 microgram/ml, respectively. Liver-function tests
remained normal or were only slightly disturbed in 11 of 12 patients treated within 10 h of paracetamol ingestion. Severe liver damage
developed in the other patient and in the three in whom treatment was started more than 10 h after paracetamol ingestion. In contrast to
cysteamine, N-acetylcysteine was very well tolerated and has the advantage of being available as a pharmaceutical preparation in a 20%
sterile solution.
Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985)
AU
Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH
SO
N Engl J Med. 1988;319(24):1557.
During the investigational use of oral N-acetylcysteine as an antidote for poisoning with acetaminophen, 11,195 cases of suspected
acetaminophen overdose were reported. We describe the outcomes of 2540 patients with acetaminophen ingestions treated with a
loading dose of 140 mg of oral N-acetylcysteine per kilogram of body weight, followed four hours later by 70 mg per kilogram given every
four hours for an additional 17 doses. Patients were categorized for analysis on the basis of initial plasma acetaminophen concentrations
and the interval between ingestion and treatment. Hepatotoxicity developed in 6.1 percent of patients at probable risk when Nacetylcysteine was started within 10 hours of acetaminophen ingestion and in 26.4 percent of such patients when therapy was begun 10
to 24 hours after ingestion. Among patients at high risk who were treated 16 to 24 hours after an acetaminophen overdose, hepatotoxicity
developed in 41 percent--a rate lower than that among historical controls. When given within eight hours of acetaminophen ingestion, Nacetylcysteine was protective regardless of the initial plasma acetaminophen concentration. There was no difference in outcome whether
N-acetylcysteine was started zero to four or four to eight hours after ingestion, but efficacy decreased with further delay. There were 11
deaths among the 2540 patients (0.43 percent); in the nine fatal cases in which aminotransferase was measured before treatment,
values were elevated before N-acetylcysteine was started. No deaths were clearly caused by acetaminophen among patients in whom Nacetylcysteine therapy was begun within 16 hours. We conclude that N-acetylcysteine treatment should be started within eight hours of
an acetaminophen overdose, but that treatment is still indicated at least as late as 24 hours after ingestion. On the basis of available
data, the 72-hour regimen of oral N-acetylcysteine is as effective as the 20-hour intravenous regimen described previously, and it may be
superior when treatment is delayed
There are reports of adult patients with massive acetaminophen ingestion (ingestion >30 g, or
serum concentration >500 mg/L [3300 μmol/L]) who develop liver injury despite early
administration of N-acetylcysteine [20,21]. Several of these cases involved coingestion
of diphenhydramine and the patients had elevated acetaminophen concentrations at the
completion of the 20 hour intravenous N-acetylcysteine protocol. Pharmacokinetic models
suggest that a higher dose of N-acetylcysteine for a longer period of time may be beneficial in
such cases [22,23]. Patients with these clinical features should be discussed with a poison
center or toxicologist familiar with the management of acetaminophen overdose. Other
medications that may worsen the outcome of acetaminophen poisoning are reviewed separately
Development of hepatic failure despite use of intravenous acetylcysteine after a massive ingestion of acetaminophen and
diphenhydramine.
AU
Schwartz EA, Hayes BD, Sarmiento KF
SO
Ann Emerg Med. 2009;54(3):421.
Acetylcysteine is an antidote used to prevent liver failure after acetaminophen overdose. We report the development of liver failure
despite administration of intravenous acetylcysteine in a patient with massive ingestion of an acetaminophen and diphenhydramine
combination product. An atypical, delayed, bimodal peak in the serum acetaminophen concentration was observed. This case suggests
that individualized dosing of antidotal therapy may be needed for preparations of acetaminophen that result in delayed absorption or after
massive overdose.
Hepatic failure despite early acetylcysteine following large acetaminophen-diphenhydramine overdose.
AU
Wang GS, Monte A, Bagdure D, Heard K
SO
Pediatrics. 2011 Apr;127(4):e1077-80. Epub 2011 Mar 14.
We describe the case of a patient with massive acetaminophen-diphenhydramine overdose and a 4-hour serum acetaminophen
concentration of 653μg/mL. The patient was treated with acetylcysteine 5 hours after ingestion. Because of a persistently elevated serum
acetaminophen level of 413μg/mL 45 hours after ingestion, a medical toxicologist recommended that the patient be treated with a second
bolus of acetylcysteine (150 mg/kg followed by 12.5 mg/kg per hour for 4 hours, then 6.25 mg/kg per hour). On hospital day 3, she
developed hepatic failure despite early treatment. Her transaminase levels and hepatic synthetic function began to improve on hospital
day 6, and acetylcysteine was discontinued on hospital day 10. In cases of massive acetaminophen overdose, standard acetylcysteine
dosing may not be adequate. We suggest that elevated serum acetaminophen concentrations at the end of a standard 20-hour
acetylcysteine infusion should be discussed with the local poison center.
ndications — Indications for N-acetylcysteine therapy include:
●Serum acetaminophen concentration drawn at four hours or more following acute
ingestion of an immediate-release preparation is above the "treatment" line of the
treatment nomogram for acetaminophen poisoning .
●A suspected single ingestion of greater than 150 mg/kg (7.5 g total dose regardless of
weight) in a patient for whom the serum acetaminophen concentration will not be available
until more than eight hours from the time of the ingestion.
●Patient with an unknown time of ingestion and a serum acetaminophen concentration
>10 mcg/mL (66µmol/L).
●Patient with a history of APAP ingestion and evidence of ANY liver injury.
●Patients with delayed presentation (>24 hours after ingestion) consisting of laboratory
evidence of liver injury (ranging from mildly elevated aminotransferases to fulminant
hepatic failure) and a history of excessive acetaminophen ingestion.
20 hour IV protocol — The 20 hour intravenous (IV) protocol for N-acetylcysteine treatment
has been used in the United Kingdom since the 1970s.
The approved 20 hour IV dosing regime is complicated and is performed as follows:
●Administer an initial loading dose of 150 mg/kg IV over 15 to 60 minutes (we recommend
60 minutes).
●Next, administer a 4 hour infusion at 12.5 mg/kg per hour IV (ie, total of 50 mg/kg over 4
hours).
●Finally, administer a 16 hour infusion at 6.25 mg/kg per hour IV (ie, total of
100 mg/kg over 16 hours).
This treatment protocol provides a total of 300 mg/kg over 20 to 21 hours [15]. The treatment
period is often extended when patients have large ingestions or elevated serum transaminase
activity. This is discussed below. (See 'Duration of treatment' below.)
72 hour oral protocol — The 72 hour oral (PO) dosing protocol for N-acetylcysteine treatment
has been used successfully in the United States for more than 30 years, and consists of the
following:
●A loading dose of 140 mg/kg PO, followed by
●A dose of 70 mg/kg PO every four hours for a total of 17 doses
The dose does not need to be adjusted if the patient has been treated with activated charcoal.
The incidence of hepatotoxicity for patients treated within eight hours of ingestion is less than 10
percent, but increases to approximately 40 percent if treatment is delayed beyond 16 hours. In
the largest study of oral N-acetylcysteine, no deaths occurred among patients treated before the
onset of transaminase elevation [11].
There are several reports describing truncated oral protocols. The duration of treatment is
discussed further below.
reatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine.
AU
Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT
SO
Lancet. 1977;2(8035):432.
Fifteen patients with paracetamol (acetaminophen) poisoning were treated with intravenous N-acetylcystein (300
mg/kg given over 20 h). Mean admission and 4 h plasma-paracetamol concentrations were 262 and 369
microgram/ml, respectively. Liver-function tests remained normal or were only slightly disturbed in 11 of 12
patients treated within 10 h of paracetamol ingestion. Severe liver damage developed in the other patient and in
the three in whom treatment was started more than 10 h after paracetamol ingestion. In contrast to cysteamine,
N-acetylcysteine was very well tolerated and has the advantage of being available as a pharmaceutical
preparation in a 20% sterile solution.
IV versus oral — There are no head-to-head trials comparing the 20 hour IV and the 72 hour
oral treatment protocols in patients treated early after ingestion. The best available data suggest
that both routes are effective and differences are minimal [25,26]. In most patients, either the
oral or IV route is acceptable. IV administration is favored for patients with any of the following:
●Vomiting
●Contraindications to oral administration (ie, pancreatitis, bowel ileus or obstruction, bowel
injury)
●Hepatic failure
●Patients who refuse oral administration
Patients with evidence of hepatic failure require IV therapy.
Effect of patient weight on dosing — Current dosing protocols for N-acetylcysteine in the
United States are calculated using patient bodyweight. However, the maximum dose is based
upon a weight of 100 kg for IV therapy and 110 kg for oral therapy [27,28]. The basis for these
recommendations is not clear, but there is no evidence that N-acetylcysteine doses calculated
with weights above these maximum amounts provide added benefit [29]. However, in a large
observational study, clinicians often based dosing on actual weight with a low rate of adverse
events [30]. Dosing based upon either the patient’s actual weight or the maximum
recommended weights described here is acceptable.
Adverse reactions — While dosing errors are common during IV Nacetylcysteine administration [31], significant adverse events stemming from such
miscalculations are rare. Non-IgE mediated anaphylaxis (previously called anaphylactoid
reactions) with intravenous administration and vomiting with oral administration are the most
common adverse reactions associated with N-acetylcysteine administration.
Anaphylaxis (anaphylactoid reaction) — Prospective studies suggest that between 10 and 20
percent of patients treated with IV N-acetylcysteine develop a hypersensitivity reaction (ie,
anaphylaxis that is not IgE-mediated, formerly known as an anaphylactoid reaction) [32,33].
Reactions vary in severity and most of these subjects are able to tolerate the infusion when it is
restarted. Nevertheless, patients receiving IV N-acetylcysteine warrant close monitoring and the
medications and equipment necessary to manage anaphylaxis should be readily available when
the initial infusion is administered
Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial.
AU
Bateman DN, Dear JW, Thanacoody HK, Thomas SH, Eddleston M, Sandilands EA, Coyle J, Cooper JG, Rodriguez A, Butcher I, Lewis
SC, Vliegenthart AD, Veiraiah A, Webb DJ, Gray A
SO
Lancet. 2014;383(9918):697.
BACKGROUND: Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is
complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to
ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or
both.
METHODS: We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012.
We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration
20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by
infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet
and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue
antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity
over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270).
FINDINGS: Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting,
retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol
compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and
in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe
anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were
allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a
50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens
(adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111;
3·30, 1·01-10·72; p=0·024).
INTERPRETATION: In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer
anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter
protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine
regimen.
Oral and Intravenous Acetylcysteine for Treatment of Acetaminophen Toxicity: A Systematic Review and Meta-analysis.
AU
Green JL, Heard KJ, Reynolds KM, Albert D
SO
West J Emerg Med. 2013 May;14(3):218-26.
Introduction: There are few reports summarizing the effectiveness of oral and intravenous (IV) acetylcysteine. We determined the
proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase>1000 IU/L) when treated with oral and
IV acetylcysteine. Methods: Studies were double abstracted by trained researchers. We determined the proportions of patients who
developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment. Results:
We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta-analysis. The overall rate of hepatotoxicity
for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity.
Conclusion: Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is
difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral
and IV administration.
Is intravenous acetylcysteine more effective than oral administration for the prevention of hepatotoxicity in acetaminophen overdose?
AU
Schwarz E, Cohn B
SO
Ann Emerg Med. 2014 Jan;63(1):79-80. Epub 2013 Aug 5.
Acetylcysteine oral solution: dosage and administration. http://www.rxlist.com/acetylcysteine-solution-drug.htm (Accessed on February
09, 2011).
Mucomyst prescribing instructions for acetaminophen overdose. Revised 24 January 2001. http://www.rxlist.com/acetylcysteine-solutiondrug.htm (Accessed on February 09, 2011).
no abstract available
Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose.
AU
Hayes BD, Klein-Schwartz W, Doyon S
SO
Ann Pharmacother. 2008;42(6):766.
BACKGROUND: Acetadote, an intravenous preparation of acetylcysteine, became commercially available in the US in June 2004 for the
treatment of acetaminophen poisoning. The dosing regimen is complex, consisting of a loading dose followed by 2 maintenance doses,
each with different infusion rates.
OBJECTIVE: To analyze the frequency of medication errors related to the complex dosing regimen for intravenous acetylcysteine.
METHODS: A retrospective chart review of a regional poison center's records was performed for all patients treated with intravenous
acetylcysteine from August 1, 2006, to August 31, 2007. Data collected included acetylcysteine dose, infusion rate, interruptions in
therapy, unnecessary administration, and medical outcome. Records that revealed medication errors were further examined for the time
and location of the errors.
RESULTS: There were 221 acetaminophen overdose cases treated with intravenous acetylcysteine that met inclusion criteria. Of these,
84 medication errors occurred in 74 (33%) patients. The frequency and types of errors were 1.4% incorrect dose, 5% incorrect infusion
rate, 18.6% more than 1 hour of interruption in therapy, and 13.1% unnecessary administration. The frequency and types of medication
errors in pediatric patients were similar to those in the total patient population. Errors occurred most frequently in the emergency
department compared with intensive care units or general medical floors. In addition, errors occurred most frequently on third shift,
compared with first or second shift. Evaluation of medical outcomes in cases involving acetaminophen only found that medication errors
did not have an impact on coded outcomes.
CONCLUSIONS: Medication administration errors occur frequently with intravenous acetylcysteine. Awareness of this problem, coupled
with increased vigilance in identifying factors associated with errors, should decrease medication errors with intravenous acetylcysteine
therapy for acetaminophen poisoning.
The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine.
AU
Kerr F, Dawson A, Whyte IM, Buckley N, Murray L, Graudins A, Chan B, Trudinger B
SO
Ann Emerg Med. 2005;45(4):402.
STUDY OBJECTIVE: We determine whether the incidence of adverse events caused by intravenous N -acetylcysteine is significantly
less when the initial dose is infused over a 60-minute period compared with the standard infusion period of 15 minutes. A secondary
objective is to assess the efficacy of the 2 treatment arms.
METHODS: This was a multicenter, randomized, prospective trial of patients who presented with acetaminophen poisoning and who
were treated with N -acetylcysteine and had no history of hypersensitivity to N-acetylcysteine. Patients were randomly assigned to
receive the initial dose of N-acetylcysteine over a 15-minute or 60-minute period. Baseline signs and symptoms and adverse events were
serially evaluated before and during administration of N -acetylcysteine. Tests of liver injury and coagulation were collected at baseline
and then at 12-hour intervals.
RESULTS: The study was designed with an 80% power to detect a halving of the incidence of adverse events. Of 180 evaluable patients,
109 patients were randomized to the 15-minute group and 71 patientswere randomized to the 60-minute group. The incidence of drugrelated adverse events was 45% in the 15-minute group and 38% in the 60-minute group (95% confidence interval -8% to 22%). The
study did not demonstrate a reduction of drug-related adverse outcomes with the 60-minute infusion. Incidence of maximum alanine
aminotransferase levels indicating hepatotoxicity (serum level>1,000 IU/L) was 6.8% (5.6% for 15-minute, 8.7% for 60-minute). The
difference did not attain statistical significance.
CONCLUSION: This study did not demonstrate a reduction of drug-related adverse outcomes with the 60-minute infusion. The study also
confirmed that early treatment with N -acetylcysteine (within 8 hours of ingestion) is more effective than later treatment.
SUMMARY AND RECOMMENDATIONS
●The initial management of acetaminophen poisoning is determined by the patient's
presenting symptoms. Patients who present within 24 hours after an acute ingestion are
generally asymptomatic. Patients who present later may manifest symptoms and signs of
hepatic injury. There are no early symptoms that predict acetaminophen toxicity; poisoning
severity in acute ingestion is quantified by plotting a timed serum acetaminophen
concentration on the modified Rumack-Matthew nomogram (figure 1). A summary table to
facilitate emergent management is provided (table 1). Risk factors for hepatotoxicity
following acetaminophen ingestion, the diagnosis of acetaminophen ingestion, and the use
of the nomogram are discussed separately
●Patients who present soon after a potentially toxic ingestion of acetaminophen (single
dose ≥7.5 g) are likely to benefit from gastrointestinal decontamination. We suggest
treatment with activated charcoal, 1g/kg (maximum dose 50 g) by mouth in all patients
who present within four hours of a known or suspected acetaminophen ingestion, unless
there are contraindications to its administration (Grade 2B).
●We recommend treatment with N-acetylcysteine for all patients
with acetaminophen poisoning at significant risk for hepatotoxicity (Grade 1A). The key to
effective treatment is to start therapy before the onset of alanine aminotransferase (ALT)
elevation. This is accomplished by initiating treatment within eight hours of an acute
ingestion. Suggestions for treatment with N-acetylcysteine in difficult clinical circumstances
(eg, time of ingestion unknown, patient is pregnant) are provided in the text (see 'Antidote
treatment in special circumstances' above). Determination of the risk for hepatotoxicity
following either acute or chronic acetaminophen ingestion is discussed separately.
)
●N-acetylcysteine may be given intravenously (IV), using a 20 hour protocol, or orally,
using a 72 hour protocol. Each protocol and its indications are described in the text.
(See '20 hour IV protocol' above and'72 hour oral protocol' above and 'IV versus
oral' above.)
●IV administration of N-acetylcysteine is favored for patients who present acutely following
an ingestion and have any of the following:
•Vomiting
•Contraindications to oral administration (ie, pancreatitis, bowel ileus or obstruction,
bowel injury)
•Patients who refuse oral administration
•In addition, patients with evidence of hepatic failure require IV therapy
●We tailor N-acetylcysteine therapy to the patient, using clinical endpoints rather than time
to determine treatment duration. In the text, we describe a treatment approach for three
common clinical scenarios based upon the type of ingestion and the clinical status of the
patient. (See 'Duration of treatment' above.)
●We routinely measure the ALT prior to stopping N-acetylcysteine and continue treatment
if the ALT is abnormal, as some patients will develop liver injury during the treatment
period. We also suggest repeating the serum acetaminophen concentration prior to
stopping N-acetylcysteine to verify that the level is undetectable. (See 'Monitoring during
treatment' above.)
●Between 10 and 20 percent of patients treated with IV N-acetylcysteine develop an
allergic or anaphylactic reaction. Management depends upon the severity of the reaction
and is described in the text. In the case of severe reactions (eg, respiratory difficulty), the
infusion should be stopped and the clinician should obtain guidance from a medical
toxicologist or poison control center. (See 'Anaphylaxis (anaphylactoid reaction)' above
and 'Additional resources' above.)
●Approximately 33 percent of subjects treated with oral N-acetylcysteine develop nausea
and vomiting. Serotonin 5-HT3 receptor antagonists (eg, ondansetron) are useful
antiemetics. If the patient vomits within 60 minutes of an oral dose of N-acetylcysteine, the
dose of N-acetylcysteine should be repeated. (See 'Vomiting' above.)
Role of mucoactive agents in the treatment of COPD
INTRODUCTION — Tracheobronchial mucus contributes significantly to the symptoms of
chronic obstructive pulmonary disease (COPD). It is a diagnostic criterion for chronic bronchitis
and one of the primary causes of airflow obstruction. In addition, chronic mucus hypersecretion
is associated with increased mortality, an accelerated decline of forced expiratory volume in one
second (FEV1), and an increased risk of hospitalization in COPD [1-3].
The role of mucoactive therapy in the management of COPD will be reviewed here. The role of
mucoactive agents in the treatment of cystic fibrosis (CF) lung disease and non-CF
bronchiectasis is discussed separately. (See "Cystic fibrosis: Overview of the treatment of lung
disease" and "Treatment of bronchiectasis in adults".)
DEFINITION — A mucoactive drug is defined as an agent with the capability of modifying
mucus production, secretion, its nature and composition, or its interactions with the mucociliary
epithelium [4]. Examples of mucoactive drugs include expectorants (induce cough or increase
the volume of secretions), mucolytics (reduce the viscosity of mucus), mucokinetic drugs
(increase the mobility and transportability of mucus), and mucoregulators (control the process of
hypersecretion) [5].
pidemiological studies in mucus hypersecretion.
AU
Vestbo J
SO
Novartis Found Symp. 2002;248:3.
Respiratory mucus in epidemiology has mainly been studied using standardized questionnaires including questions on cough and
phlegm. In chronic obstructive pulmonary disease (COPD) much controversy exists regarding the importance of mucus hypersecretion.
From being the key element in the 'British hypothesis' it was reduced to being an innocent disorder in the 1980s but is now again
recognized as a potential risk factor for an accelerated loss of lung function. Whereas early studies in mainly occupational cohorts
showed no effect of chronic mucus hypersecretion on decline in lung function, such an effect has been shown in subsequent studies on
general population samples. Chronic mucus hypersecretion also increases risk of hospital admission which may be due to an increased
risk of lower respiratory tract infection. In severe COPD this may explain the increased mortality associated with the presence of mucus.
In asthma recent findings suggest that in epidemiology chronic mucus hypersecretion may indicate lack of control which leads to an
accelerated loss of lung function and increased mortality in subjects with self-reported asthma.
he nature of small-airway obstruction in chronic obstructive pulmonary disease.
AU
Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, ParéPD
SO
N Engl J Med. 2004;350(26):2645.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health problem associated with long-term exposure to
toxic gases and particles. We examined the evolution of the pathological effects of airway obstruction in patients with COPD.
METHODS: The small airways were assessed in surgically resected lung tissue from 159 patients--39 with stage 0 (at risk), 39 with stage
1, 22 with stage 2, 16 with stage 3, and 43 with stage 4 (very severe) COPD, according to the classification of the Global Initiative for
Chronic Obstructive Lung Disease (GOLD).
RESULTS: The progression of COPD was strongly associated with an increase in the volume of tissue in the wall (P<0.001) and the
accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways. The percentage of the airways that
contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells
(P<0.001), and lymphoid aggregates containing follicles (P=0.003) and the absolute volume of B cells (P=0.03) and CD8 cells (P=0.02)
also increased as COPD progressed.
CONCLUSIONS: Progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and
infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles. These changes are coupled to a
repair or remodeling process that thickens the walls of these airways.
Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology.
AU
Hogg JC, Chu FS, Tan WC, Sin DD, Patel SA, Pare PD, Martinez FJ, Rogers RM, Make BJ, Criner GJ, Cherniack RM, Sharafkhaneh A,
Luketich JD, Coxson HO, Elliott WM, Sciurba FC
SO
Am J Respir Crit Care Med. 2007;176(5):454.
RATIONALE: COPD is associated with reduced life expectancy.
OBJECTIVES: To determine the association between small airway pathology and long-term survival after lung volume reduction in
chronic obstructive pulmonary disease (COPD) and the effect of corticosteroids on this pathology.
METHODS: Patients with severe (GOLD-3) and very severe (GOLD-4) COPD (n = 101) were studied after lung volume reduction
surgery. Respiratory symptoms, quality of life, pulmonary function, exercise tolerance, chest radiology, and corticosteroid treatment
status were assessed preoperatively. The severity of luminal occlusion, wall thickening, and the presence of small airways containing
lymphoid follicles were determined in resected lung tissue. Kaplan-Meier survival analysis and Cox proportional hazards models were
used to determine the relationship between survival and small airway pathology. The effect of corticosteroids on this pathologywas
assessed by comparing treated and untreated groups.
MEASUREMENTS AND MAIN RESULTS: The quartile of subjects with the greatest luminal occlusion, adjusted for covariates, died
earlier than subjects who had the least occlusion (hazard ratio, 3.28; 95% confidence interval, 1.55-6.92; P = 0.002). There was a trend
toward a reduction in the number of airways containing lymphoid follicles (P = 0.051) in those receiving corticosteroids, with a statistically
significant difference between the control and oral +/- inhaled corticosteroid-treated groups (P = 0.019). However, corticosteroid
treatment had no effect on airway wall thickening or luminal occlusion.
CONCLUSIONS: Occlusion of the small airways by inflammatory exudates containing mucus is associated with early death in patients
with severe emphysema treated by lung volume reduction surgery. Corticosteroid treatment dampens the host immune response in these
airways by reducing lymphoid follicles without changing wall thickening and luminal occlusion.
Mucoactive agents for airway mucus hypersecretory diseases.
AU
Rogers DF
SO
Respir Care. 2007;52(9):1176.
Airway mucus hypersecretion is a feature of a number of severe respiratory diseases, including asthma, chronic obstructive pulmonary
disease (COPD), and cystic fibrosis (CF). However, each disease has a different airway inflammatory response, with consequent, and
presumably linked, mucus hypersecretory phenotype. Thus, it is possible that optimal treatment of the mucus hypersecretory element of
each disease should be disease-specific. Nevertheless, mucoactive drugs are a longstanding and popular therapeutic option, and
numerous compounds (eg, N-acetylcysteine, erdosteine, and ambroxol) are available for clinical use worldwide. However, rational
recommendation of these drugs in guidelines for management of asthma, COPD, or CF has been hampered by lack of information from
well-designed clinical trials. In addition, the mechanism of action of most of these drugs is unknown. Consequently, although it is possible
to categorize them according to putative mechanisms of action, as expectorants (aid and/or induce cough), mucolytics (thin mucus),
mucokinetics (facilitate cough transportability), and mucoregulators (suppress mechanisms underlying chronic mucus hypersecretion,
such as glucocorticosteroids), it is likely that any beneficial effects are due to activities other than, or in addition to, effects on mucus. It is
also noteworthy that the mucus factors that favor mucociliary transport (eg, thin mucus gel layer, "ideal" sol depth, and elasticity greater
than viscosity) are opposite to those that favor cough effectiveness (thick mucus layer, excessive sol height, and viscosity greater than
elasticity), which indicates that different mucoactive drugs would be required for treatment of mucus obstruction in proximal versus distal
airways, or in patients with an impaired cough reflex. With the exception of mucoregulatory agents, whose primary action is unlikely to be
directed against mucus, well-designed clinical trials are required to unequivocally determine the effectiveness, or otherwise, of
expectorant, mucolytic, and mucokinetic agents in airway diseases in which mucus hypersecretion is a pathophysiological and clinical
issue. It is noteworthy that, of the more complex molecules in development, it is simple inhaled hypertonic saline that is currently
receiving the greatest attention as a mucus therapy, primarily in CF.
MUCOACTIVE EFFECTS OF ROUTINE TREATMENTS FOR COPD — In COPD, the most
important intervention to reduce sputum production is cigarette smoking cessation [18]. Some
routine therapies for COPD, in addition to their bronchodilator or anti-inflammatory effects, also
have mucoactive effects.
Bronchodilators act as mucokinetic agents by improving airflow and facilitating mucus
clearance. The different types of bronchodilators have additional, more specific effects that may
be either beneficial or detrimental.
Beta agonists — Beta agonists improve clearance of airway mucus largely via an effect on
ciliary beat frequency. As an example, aerosolized isoproterenol (a potent sympathomimetic
amine with almost exclusive ß-adrenergic activity) increases mucus clearance, presumably from
increased ciliary beat rate [19]. This effect is not due to bronchial vasodilation, the presence of
aqueous aerosol droplets, reflex parasympathetic activation, or bronchodilation [19,20].
Anticholinergics — The anticholinergic agent atropine is an effective antisialagogue (reduces
saliva secretion) that results in significant reductions in tracheal mucus velocity and mucociliary
transport [21,22]. However, it has no effect on mucus secretory rate [21].
Ipratropium bromide does not appear to have the same effects as atropine. As an example,
studies in humans have not detected changes in the clearance of secretions or in sputum
volume or viscosity [23], while animal studies have shown only minimal depression of ciliary
beat frequency and tracheal mucus velocity, with no effect on volume or viscoelastic properties
[21]. Thus, ipratropium bromide can improve airway obstruction without negatively affecting
mucociliary clearance [20].
In small studies, the effect of tiotropium on mucociliary clearance (as measured by radioaerosol
clearance) was not different from placebo, but tiotropium was inferior to formoterol [24,25]. It is
not known whether this is a clinically important effect.
Methylxanthines — Methylxanthines stimulate ciliary beat frequency and increase water flux
toward the lumen, which should improve mucus clearance, but they also increase mucus
secretion in the lower airways [26]. However, some of these effects depend on a relatively high
dose that causes gastric irritation (and thus a vagally-mediated increase in airway secretions),
rather than on the bronchodilator effect. Overall, oralaminophylline increases tracheobronchial
mucociliary clearance in patients with COPD, but this effect is not associated with identifiable
improvement in pulmonary function or cough [27]. The role of methylxanthines in COPD is more
related to improvement in exercise tolerance than to improved secretion clearance or reduction
in the frequency of exacerbations.
Phosphodiesterase inhibitors — The phosphodiesterase (PDE)4 inhibitor roflumilast,
although not a mucoactive agent, was found to be most effective in patients with repeated
exacerbations of COPD and with a chronic bronchitis phenotype, consisting of high cough or
sputum scores [28]. Randomized trials have confirmed that the use of roflumilast in such
patients reduced the exacerbation frequency, improved the FEV1, and improved the dyspnea
scores [29].
Inhaled glucocorticoids — Glucocorticoids can act as a mucoregulator by affecting the
underlying cause of mucus hypersecretion. Aerosolized beclomethasone at doses
>800 mcg/day has been shown to produce a significant improvement in spirometry in patients
with chronic bronchitis [30]. The benefit appears to result from control of airway inflammation
since beclomethasone does not affect mucociliary clearance [31]
MUCOACTIVE AGENTS OF LIMITED OR NO BENEFIT — A number of modalities, including
hydration, hypertonic saline inhalation, oral expectorants, oral iodide preparations,
cromoglycate, and inhalation of DNAse, have been utilized to alter the characteristics of mucus,
but without evidence of substantial clinical efficacy.
Hydration — While maintaining normal hydration is appropriate, there is no evidence that
overhydration in order to facilitate sputum production is of any benefit. One study, for example,
evaluated the effect of hydration on mucus volume, viscoelastic properties of sputum,
respiratory symptoms, and forced expiratory volume in one second (FEV1): there were no
differences when patients were dehydrated, were treated with hydration (1800 to
2400 mL/day), or had ad lib fluid intake [59].
Hypertonic saline — Hypertonic saline aerosols have traditionally been used to induce
expectoration of sputum for diagnostic evaluation [60]. The effects of hypertonic saline that aid
the clearance of sputum include [35,61,62]:
●Stimulation of a productive cough
●Decreased sputum spinnability (ability to be spun into a strand)
●Decreased sputum viscoelasticity
Despite these effects and the benefits in cystic fibrosis, there is no evidence of any therapeutic
value of hypertonic saline aerosols in COPD [62-64]. In addition, the administration of either
isotonic or hypertonic aerosols can induce a significant decrease in lung function in patients with
COPD due to bronchoconstriction [65]. This deleterious effect may be mast cell-mediated, since
the decrease in lung function was most pronounced in patients with increased histamine in their
sputum. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Inhaled
hypertonic saline'.)
Oral expectorants — Oral expectorants, such as guaifenesin, bromhexine, ipecac, and
ammonium salts stimulate the gastric nerve and promote a vagally-mediated increase in airway
secretions [9]. As a corollary, all of these agents are actually emetics [66]. Other mechanisms of
action may include a reduction in mucus viscosity [9] or an enhancement of the mucociliary
elevator [35].
Despite these mucolytic actions, the limited clinical trial data available provide little evidence
that oral expectorants improve lung function or subjective well-being in COPD [9,35]. In one
study, for example, both bromhexine and guaifenesin improved tracheobronchial clearance but
did not change lung function, the frequency of cough, emotional well-being, or the weight and
content of sputum [35]. However, in an older report, bromhexine reduced viscosity of mucus,
increased mucus output, and improved spirometric indices in patients with moderate airway
obstruction [67].
Iodide preparations — Iodide acts as a mucolytic by decreasing the viscosity of mucus,
facilitating the breakdown of proteins by proteolytic enzymes, and increasing ciliary beat
frequency [68]. Iodine preparations include saturated solution of potassium iodide (SSKI),
domiodol, and iodopropylidene glycerol. Due to their adverse effect profile, they are not
recommended for use as mucolytic agents in COPD.
●SSKI may decrease the viscosity of mucus, but its use is limited by side effects such as a
metallic taste, rash, hyperkalemia (in patients with renal insufficiency), and
hypothyroidism, particularly if use is prolonged for more than six weeks.
●Domiodol is an organic iodinated mucolytic agent. When administered to
tracheostomized patients after laryngectomy, this agent improved cough intensity, sputum
quantity and quality, as well as ease of expectoration [69]. It is not available for clinical
use.
●Iodopropylidene glycerol has been shown to enhance tracheobronchial clearance and
mucociliary transport in expectorating patients with chronic bronchitis [68]. In addition, a
randomized, double-blind placebo-controlled study documented improvements in cough,
ease of expectoration, and well-being, and a decreased duration of exacerbations [70].
However, in a subsequent randomized, cross-over study, the use of iodinated glycerol for
16 weeks did not improve pulmonary function, well being, or sputum viscoelasticity or
clearability [71]. This drug is no longer available in the United States after concerns were
raised about carcinogenesis in selected strains of rats and mice.
Sodium cromoglycate — Sodium cromoglycate can improve the depressed tracheal mucus
velocity in asthmatics [72]. However, the clinical significance of this finding is uncertain, and
sodium cromoglycate has limited availability. (See "The use of chromones (cromoglycates) in
the treatment of asthma".)
Recombinant human DNase — DNA released by leukocytes is thought to contribute
significantly to the viscosity of mucus in patients with cystic fibrosis (CF). Thus, recombinant
human DNase is considered a mucokinetic agent that may produce improvement in pulmonary
function in patients with clinically stable CF. However, recombinant human DNase does not
appear to be effective in the management of non-CF bronchiectasis, and data are lacking
regarding its use in COPD. (See "Cystic fibrosis: Overview of the treatment of lung disease",
section on 'Inhaled DNase I (dornase alfa)' and "Treatment of bronchiectasis in adults", section
on 'Mucolytic agents and airway hydration'.)
EXPERIMENTAL MUCOACTIVE AGENTS — Several agents that are mucoactive in the
laboratory are being evaluated for clinical use.
Surfactant — A surfactant layer is present between layers of mucus gel and periciliary sol fluid,
serving to separate these two layers and to facilitate mucus spreading [7,11]. The lubricant
properties of surfactant also promote the transfer of energy from beating cilia to mucus [11].
(See 'Properties of mucus' above.)
Several observations suggest a potential role for surfactant as a mucoactive substance,
although this use of surfactant remains experimental:
●A decrease in surface-active phospholipid fractions in the sputum of patients with CF
(compared with sputum from patients with COPD) has been found to correlate with
increased mucus stasis [73].
●Tracheal instillation of surfactant in anesthetized dogs significantly increases ciliary beat
frequency compared to instillation of normal saline [74].
●One randomized, double-blind study of 66 patients with stable chronic bronchitis
compared the effectiveness of two weeks of thrice daily, nebulized phosphatidylcholine
surfactant (Exosurf) versus placebo [75]. The treatment group had increased in vitro
sputum transportability, improvement in pre- and postbronchodilator FEV1 and FVC by >10
percent, and mildly decreased RV/TLC ratios. The high cost of exogenous surfactant
precludes its routine use in patients with chronic bronchitis until its salutary effects are
better defined in larger trials.
Actin-severing agents — Gelsolin is an actin-severing agent that has been shown in vitro to
reduce the viscosity of sputum samples from patients with CF [76]. This effect presumably
reflects the presence of filamentous actin in CF sputum. The clinical applicability and
effectiveness of gelsolin remain to be determined.
Prostaglandin inhibitors — Airway secretion may depend partially on endogenous
prostaglandins. Blockade of the cyclooxygenase pathway by the use of
inhaled indomethacin was found to decrease the amount of expectorated sputum and to
improve perceived dyspnea [77,78]. The long-term effects of such therapy are unknown, and
further information is needed before this treatment modality can be generalized [77].
A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis.
AU
Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova
EG, Xuan W, Bye PT, National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study
Group
SO
N Engl J Med. 2006;354(3):229.
BACKGROUND: Inhaled hypertonic saline acutely increases mucociliary clearance
and, in short-term trials, improves lung function in people with cystic fibrosis. We
tested the safety and efficacy of inhaled hypertonic saline in a long-term trial.
METHODS: In this double-blind, parallel-group trial, 164 patients with stable cystic
fibrosis who were at least six years old were randomly assigned to inhale 4 ml of either
7 percent hypertonic saline or 0.9 percent (control) saline twice daily for 48 weeks, with
quinine sulfate (0.25 mg per milliliter) added to each solution to mask the taste. A
bronchodilator was given before each dose, and other standard therapies were continued
during the trial.
RESULTS: The primary outcome measure, the rate of change (slope) in lung function
(reflected by the forced vital capacity [FVC], forced expiratory volume in one second
[FEV1], and forced expiratory flow at 25 to 75 percent of FVC [FEF25-75]) during the
48 weeks of treatment, did not differ significantly between groups (P=0.79). However,
the absolute difference in lung function between groups was significant (P=0.03) when
averaged across all post-randomization visits in the 48-week treatment period. As
compared with the control group, the hypertonic-saline group had significantly higher
FVC (by 82 ml; 95 percent confidence interval, 12 to 153) and FEV1 (by 68 ml; 95
percent confidence interval, 3 to 132) values, but similar FEF25-75 values. The
hypertonic-saline group also had significantly fewer pulmonary exacerbations (relative
reduction, 56 percent; P=0.02) and a significantly higher percentage of patients without
exacerbations (76 percent, as compared with 62 percent in the control group; P=0.03).
Hypertonic saline was not associated with worsening bacterial infection or
inflammation.
CONCLUSIONS: Hypertonic saline preceded by a bronchodilator is an inexpensive,
safe, and effective additional therapy for patients with cystic fibrosis.
(ClinicalTrials.gov number, NCT00271310.)
AD
Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, Australia.
PMID
16421364
64
PubMed
TI
Mucus clearance and lung function in cystic fibrosis with hypertonic saline.
AU
Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC
SO
N Engl J Med. 2006;354(3):241.
BACKGROUND: Abnormal homeostasis of the volume of airway surface liquid in patients with cystic fibrosis is thought to produce
defects in mucus clearance and airway defense. Through osmotic forces, hypertonic saline may increase the volume of airway surface
liquid, restore mucus clearance, and improve lung function.
METHODS: A total of 24 patients with cystic fibrosis were randomly assigned to receive treatment with inhaled hypertonic saline (5 ml of
7 percent sodium chloride) four times daily with or without pretreatment with amiloride. Mucus clearance and lung function were
measured during 14-day baseline and treatment periods.
RESULTS: Long-term inhalation of hypertonic saline without pretreatment with amiloride (i.e., with placebo pretreatment) resulted in a
sustained (>or =8 hours) increase in 1-hour rates of mucus clearance, as compared with those with amiloride pretreatment (14.0+/-2.0
vs. 7.0+/-1.5 percent, respectively; P=0.02) and increased 24-hour rates of mucus clearance over baseline. Furthermore, inhalation of
hypertonic saline with placebo improved the forced expiratory volume in one second (FEV1) between the baseline period and the
treatment period (mean difference, 6.62 percent; 95 percent confidence interval, 1.6 to 11.7; P=0.02), whereas hypertonic saline with
amiloride did not improve FEV1 (mean difference, 2.9 percent; 95 percent confidence interval, -2.2 to 8.0; P=0.23). Forced vital capacity
(FVC), the forced expiratory flow between 25 and 75 percent of FVC (FEF25-75), and respiratory symptoms also significantly improved in
patients treated with hypertonic saline and placebo, whereas the residual volume as a proportion of total lung capacity (RV:TLC) did not
change in either group. A comparison of the changes in lung function in the two groups showed no significant difference. In vitro data
suggested that sustained hydration of airway surfaces was responsible for the sustained improvement in mucus clearance, whereas
inhibition of osmotically driven water transport by amiloride accounted for the observed loss of clinical benefit.
CONCLUSIONS: In patients with cystic fibrosis, inhalation of hypertonic saline produced a sustained acceleration of mucus clearance
and improved lung function. This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease.
High-frequency oscillation of the airway and chest wall.
AU
Fink JB, Mahlmeister MJ
SO
Respir Care. 2002 Jul;47(7):797-807.
High-frequency oscillation (HFO), applied to either the airway or chest wall, has been associated with changes in sputum attributes and
clearance. The evolution of evidence, both in vitro and in vivo, supporting the use of HFO is reviewed. Devices that apply HFO to the
airway range from the relatively simple mechanical Flutter and Acapella devices to the more complex Percussionaire Intrapercussive
Ventilators. and the Hayek Oscillator are designed to provide high-frequency chest wall compression. Operation and use of these devices
are described with examples of differentiation of device types by characterization of flows, and airway and esophageal pressures.
Although HFO devices span a broad range of costs, they provide a reasonable therapeutic option to support secretion clearance for
patients with cystic fibrosis.
AD
Aerogen Incorporated, Mountain View, California 94043, USA. [email protected]
PMID
12088550
80
PubMed
TI
Mechanical behaviors of Flutter VRP1, Shaker, and Acapella devices.
AU
dos Santos AP, Guimarães RC, de Carvalho EM, Gastaldi AC
SO
Respir Care. 2013 Feb;58(2):298-304.
BACKGROUND: Flutter VRP1, Shaker, and Acapella are devices that combine positive expiratory pressure (PEP) and oscillations.
OBJECTIVES: To compare the mechanical performance of the Flutter VRP1, Shaker, and Acapella devices.
METHODS: An experimental platform and a ventilator, used a flow generator at 5, 10, 15, 20, 26, and 32 L/min, were employed at angles
of -30°, 0°, and +30°to evaluate Flutter VRP1 and Shaker, whereas Acapella was adjusted at intermediate, higher, and lower levels of
resistance, including positive expiratory pressures (PEP) along with air outflow rates and oscillation frequencies.
RESULTS: When the relationships between pressure amplitudes of all air flows were analyzed for the 3 devices at low and intermediate
pressures levels, no statistically significant differences were observed in mean pressure amplitudes between Flutter VRP1 and Shaker
devices. However, both devices had different values from Acapella, with their pressure amplitude values being higher than that of
Acapella (P = .04). There were no statistically significant differences in PEP for the 3 angles or marks regarding all air flows. The
expected relationships between variables were observed, with increases in PEP, compared to those of air flows and resistance.
Nevertheless, there was a statistically significant difference in frequency of oscillation between these devices and Acapella, whose value
was higher than those of Flutter VRP1 and Shaker devices (P = .002). At intermediate pressure levels, the patterns were the same, in
comparison to low pressures, although the Acapella device showed frequencies of oscillation values lower than those of Flutter VRP1
and Shaker (P<.001). At high pressures, there were no statistically significant differences among the 3 devices for frequency of
oscillations.
CONCLUSIONS: The Flutter VRP1 and Shaker devices had a similar performance to that of Acapella in many aspects, except for PEP.
MECHANICAL DEVICES TO IMPROVE MUCUS CLEARANCE — Chest physiotherapy
devices, such as oscillating devices, external percussion vests, and intrapulmonary percussive
ventilation, have been the cornerstone of secretion removal in cystic fibrosis and other forms of
bronchorrhea, although data in support of their use in COPD is limited. We occasionally use
oscillating devices (eg, flutter or Acapella devices) for patients with COPD who have tenacious
or copious sputum. Patients breathe in and out through the device for several larger than tidal
volume breaths and then expectorate any sputum that has been raised.
Devices that achieve airflow oscillation have favorable effects on the viscoelasticity of sputum
both in vivo and in vitro and increase mucus movement [79,80]. Further studies are needed in
patients with COPD to determine whether such devices decrease the frequency of
exacerbations and/or improve cough, mucus clearance, and quality of life [81,82].
In a study of 23 patients with severe COPD, use of a flutter device led to improved spirometry
within a few minutes and at 120 minutes after administration of bronchodilators by metered
dose inhaler [83]. A greater improvement in six minute walk distance was also noted in the
subjects who used the flutter device, although the change was of borderline clinical significance.
Further study is needed to determine whether use of devices like the flutter valve immediately
prior to inhaled bronchodilator would improve exercise tolerance and quality of life.
Use of a mucus clearance device enhances the bronchodilator response in patients with stable COPD.
AU
Wolkove N, Kamel H, Rotaple M, Baltzan MA Jr
SO
Chest. 2002;121(3):702.
STUDY OBJECTIVE: To determine whether the use of a mucus clearance device (MCD) [Flutter; Axcan Scandipharm; Birmingham,
AL]could improve the bronchodilator response to inhaled ipratropium and salbutamol delivered by a metered-dose inhaler in patients with
stable, severe COPD.
PATIENTS: Twenty-three patients with severe COPD were studied. Mean +/- SD age was 71.7 +/- 6.3 years. Mean FEV(1) was 0.74 +/0.28 L or 34.5 +/- 12.7% predicted.
METHODS: Patients were tested in random order on 2 subsequent days after using an MCD or a sham MCD. A bronchodilator (four
puffs; each puff delivering 20 microg of ipratropium bromide and 120 microg of salbutamol sulfate) was administered by metered-dose
inhaler with a holding chamber after use of the MCD or sham MCD. Spirometry was performed before and after use of the MCD or sham
MCD, and at 30 min, 60 min, and 120 min after the bronchodilator. Six-minute walk distance was tested between 30 min and 60 min;
oxygen saturation, pulse, and a dyspnea score were recorded before and after walking.
RESULTS: Immediately after use of the MCD, but not the sham MCD, there was a statistically significant (p<0.05) improvement in
FEV(1) and FVC (11 +/- 24% vs 1 +/- 7% and 18 +/- 33% vs 6 +/- 18%, respectively). Whether patients were pretreated with the MCD or
sham MCD, there was a significant improvement in FEV(1) and FVC compared to baseline with combined bronchodilator therapy. At 120
min, the change in FEV(1) after treatment with the MCD was greater than with the sham MCD (186 +/- 110 mL vs 130 +/- 120 mL;
p<0.05). When comparing the MCD to the sham MCD, 6-min walk distance was greater (174 +/- 92 m vs 162 +/- 86 m; p<0.05), with less
dyspnea before and at the end of walking.
CONCLUSION: Patients with severe COPD may demonstrate a significant bronchodilator response to combined ipratropium and
salbutamol delivered by metered-dose inhaler. This response may be enhanced and additional functional improvement obtained with the
prior use of a bronchial MCD.
SUMMARY AND RECOMMENDATIONS
●Increased tracheobronchial mucus contributes to the disease burden of COPD.
●General recommendations for treating excess mucus in COPD focus on the treatment of
underlying airways obstruction, airway inflammation, and mucus production by the use of
cigarette smoking cessation and guideline-based use of bronchodilator therapy and
inhaled glucocorticoids, as well as the occasional use of methylxanthines or
phosphodiesterase-4 inhibitors.
●Antibiotic therapy helps in acute exacerbations of COPD associated with increased
sputum volume or purulence by reducing the bacterial load that contributes to
inflammation and sputum production. In addition, long-term antibiotic therapy may reduce
the rate of exacerbations among selected patients who have more than two exacerbations
a year.
●We do not routinely use oral thiol preparations in patients with COPD. However, for
patients with bothersome sputum production that is refractory to smoking cessation,
routine therapies for COPD, and a course of antibiotics (when indicated), therapy with an
oral thiol preparation (eg, N-acetyl cysteine [NAC], 600 mg twice daily) can be initiated on
a trial basis and continued if there is symptomatic improvement. Side effects of thiol
preparations include nausea, vomiting, and allergic reactions. We avoid nebulized NAC
due to the potential for acute bronchospasm.
●While over-hydration provides no benefit in sputum clearance for patients with COPD,
avoiding dehydration is appropriate. Modalities, such as hypertonic saline inhalation, oral
expectorants (eg,guaifenesin), oral iodide preparations (eg, SSKI), inhaled cromoglycate,
and inhalation of DNAse, may alter the characteristics of mucus but lack substantial
evidence of clinical efficacy.
●Future therapies may include agents that decrease sputum adhesiveness or
viscosity and/or decrease sputum production, such as surfactants, actin-severing agents,
and prostaglandin inhibitors.
●Oscillating (eg, flutter valve, acapella device) and other mechanical devices have been
used in bronchiectasis to aid in airway clearance. It is not known whether such therapy
would be beneficial in patients with COPD. We occasionally use oscillating devices for
patients with COPD who have tenacious or copious sputum. Patients breathe in and out
through the device for several larger than tidal volume breaths then expectorate any
sputum that has been raised.
Acetylcysteine — Acetylcysteine is a thiol compound with antioxidant and vasodilatory
properties. Although not well understood, a possible mechanism of benefit in contrast-induced
nephropathy involves minimizing both vasoconstriction and oxygen-free radical generation after
radiocontrast agent administration.
There are great heterogeneity and conflicting results in the available clinical trials and metaanalyses examining the effectiveness of acetylcysteine in the prevention of contrast
nephropathy [60,61]. Given the conflicting data regarding benefit, we cannot make a strong
recommendation regarding the use of acetylcysteine. Since the agent is potentially beneficial,
well tolerated, and relatively inexpensive, we agree with the 2012 KDIGO guidelines that
suggest administration of acetylcysteine to patients at high risk. However, some clinicians may
elect not to give this unproven therapy [24]. The joint ACC/AHA guidelines do not recommend
acetylcysteine [62].
This must be accompanied by intravenous isotonic fluid administration and use of a low- or isoosmolal contrast agent. (See "Pathogenesis, clinical features, and diagnosis of contrast-induced
nephropathy", section on 'Epidemiology' and 'Our approach to fluid administration' above
and 'Type of contrast agent' above.)
Numerous prospective trials examining the prophylactic effect of acetylcysteine in contrast
nephropathy have been performed, with substantial inconsistency in reported results [63-76]. A
variety of factors probably contribute to these inconsistencies. These include the definition of
contrast-induced AKI; baseline risk for AKI (eg, severity of renal dysfunction and proportion with
diabetes); acetylcysteine dose and route of administration (eg, oral or intravenous); intravenous
volume administration protocols; amount and type of contrast given; and type of procedure
performed (eg, contrast CT, cardiac catheterization, or peripheral angiography) [14,77,78].
In the Acetylcysteine for the Prevention of Contrast-Induced Nephropathy (ACT) trial, 2308
patients undergoing angiography received either acetylcysteine (1200 mg orally twice daily) or
placebo on the day before and after angiogram [79]. Patients had at least one of the following
risk factors: age >70 years, CKD, diabetes mellitus, heart failure or LV ejection fraction <45
percent, or shock. There was no difference in the development of AKI, defined as a ≥25 percent
increase above baseline in serum creatinine within 48 to 96 hours after angiography (12.7
percent in both groups). Secondary endpoints, including death, the need for dialysis, or either at
30 days, were also not different between groups.
There was no difference among groups in several subgroups that were defined after the study
ended, including the following:
●Patients with CKD, defined as baseline serum creatinine ≥1.5 mg/dL (n = 367; 6.4 versus
5.6 percent in placebo)
●Patients with stage 3 CKD, defined as an eGFR between 30 and 60 mL/min/1.73 m2 (n =
823; 7.1 versus 6.8 percent in placebo)
●Patients with stage 4 CKD, defined as an eGFR <30 mL/min/1.73 m2 (n = 104; 10.7
versus 6.3 in placebo)
●Patients with diabetes mellitus
However, this trial has several shortcomings:
●Although 823 patients had CKD as defined by eGFR, only 367 patients had a serum
creatinine >1.5mg/dL. Thus, the majority of patients defined as having CKD had only a
mild reduction in eGFR (ie, 45 to 60 mL/min/1.73 m2). It is not clear whether such patients
are at increased risk for contrast nephropathy. A benefit of acetylcysteine would not be
expected to be seen among patients who are not at risk.
●The incidence of AKI in patients with CKD, defined by a serum creatinine
>1.5 mg/dL (who are more likely to have eGFR <45 mL/min/1.73 m2), was low, suggesting
that the trial was underpowered to exclude a benefit of acetylcysteine for patients at
highest risk for AKI.
●The baseline creatinine was obtained at any time within three months of angiography
and, thus, may not have provided an accurate reference serum creatinine for assessing
the postprocedural change.
●Over 20 percent of patients received high-osmolal contrast media, which confers a
greater risk for AKI compared with low- or iso-osmolal media. (See 'Type of contrast
agent' above.)
The overall prophylactic efficacy of acetylcysteine has been assessed in multiple metaanalyses. Several meta-analyses have suggested a substantial benefit, reporting risk reductions
of up to 50 percent with acetylcysteine, whereas others have reported less substantial, and
occasionally nonsignificant, risk reductions [46,79-84]. In general, benefits have been reported
in meta-analyses that did not consider the great heterogeneity between the trials [85].
However, benefits have also been noted in some, but not all, meta-analyses that did recognize
this heterogeneity [83,84,86,87]. In one meta-analysis that included 41 studies, but was
published before the ACT trial, N-acetylcysteine significantly lowered the risk for contrast
nephropathy compared with saline alone (RR 0.62, 95% CI 0.44-0.88) [86].
A potential concern related to the interpretation of clinical trials is that administration
of acetylcysteine in typical doses (600 mg twice daily for two days) transiently reduces the
serum creatinine [63,64,70,88]. However, the magnitude of the fall in serum creatinine is very
small (eg, from 0.85 to 0.82 mg/dL [75 to 72 micromol/L] in a study in normal patients [88]) in
comparison with the ≥25 to 50 percent increase used to define contrast nephropathy in clinical
trials. Higher doses of acetylcysteine (1200 mg twice daily for two days) also had virtually no
effect on serum creatinine among patients with eGFR <60 mL/min/1.73 m2 [89].
Dosing — A variety of different dosing regimens for oral acetylcysteine have been studied. The
most commonly studied dose is 600 mg orally twice daily. A subgroup analysis of 12 studies
that evaluated this regimen reported a summary risk ratio of 0.73 (95% CI 0.46-1.2) [83].
However, studies comparing 600 and 1200 mg twice daily suggested slightly better outcomes
with the higher dose [74,75]. A beneficial effect of high-dose acetylcysteine compared with
control has also been shown. The best data are from a meta-analysis of 1677 subjects that
compared the effect of high-dose acetylcysteine (defined as a daily dose >600 mg or a single
preprocedural dose >600 mg) with control [90]. The majority (>70 percent) of subjects had CKD
at baseline. The risk of contrast nephropathy was lower among subjects who received highdose acetylcysteine compared with those who did not (OR 0.46, 95% CI 0.33-0.64).
Although data regarding the efficacy of acetylcysteine are conflicting, if it is to be used, the
preferred dose is 1200 mg administered orally twice daily on the day before and the day of the
procedure to patients at risk for contrast nephropathy.
Prevention of contrast-induced nephropathy
Patients with near-normal renal function are at little risk of contrast nephropathy, and few
precautions are necessary, other than avoidance of volume depletion.
(See "Pathogenesis, clinical features, and diagnosis of contrast-induced nephropathy",
section on 'Epidemiology'.)
●Patients at increased risk of contrast nephropathy include those with a serum creatinine
≥1.5 mg/dL (132micromol/L) or an estimated glomerular filtration rate (eGFR) <60 mL/1.73
m2, particularly in those with diabetes. (See "Pathogenesis, clinical features, and diagnosis
of contrast-induced nephropathy", section on 'Epidemiology'.)
●For at-risk patients, we recommend the following preventive measures:
•When possible, use ultrasonography, magnetic resonance imaging
(MRI) without gadolinium contrast, or computed tomography (CT)
scanning without radiocontrast agents. (See 'General measures' above.)
•We recommend not using high-osmolal agents (1400 to 1800 mosmol/kg) (Grade
1A). (See 'Type of contrast agent' above.)
•We recommend the use of iodixanol or nonionic low-osmolal agents, such
as iopamidol or ioversol, rather than iohexol (Grade 1B). (See 'Nonionic iso-osmolal
agents' above.)
•Use lower doses of contrast and avoid repetitive, closely spaced studies (eg, <48
hours apart). (See'General measures' above.)
•Avoid volume depletion and nonsteroidal anti-inflammatory drugs (NSAIDs).
(See 'General measures' above.)
•If there are no contraindications to volume expansion, we recommend isotonic
intravenous fluids prior to and continued for several hours after contrast
administration (Grade 1B). Either isotonic bicarbonate or isotonic NaCl may be used,
although there is a slight preference for isotonic NaCl, since NaCl is less expensive
and there is no risk of compounding errors. There are no commercially available
isotonic sodium bicarbonate solutions available, and, if bicarbonate is used, care
must be taken to avoid compounding errors in preparing solutions. (See 'Our
approach to fluid administration'above and 'Intravenous bicarbonate' above.)
Timing and rate of administration are independent of fluid type and vary between
inpatients and outpatients:
-Among outpatients, we give 3 mL/kg over one hour preprocedure and 1 to
1.5 mL/kg/hourduring and for four to six hours postprocedure, with
administration of at least 6 mL/kgpostprocedure, regardless of fluid type.
-Among inpatients, we give 1 mL/kg/hour for 6 to 12 hours preprocedure,
intraprocedure, and for 6 to 12 hours postprocedure. (See 'Intravenous
bicarbonate' above.)
•Despite conflicting data, we suggest that acetylcysteine be administered the day
before and the day of the procedure, based upon its potential for benefit and low
toxicity and cost (Grade 2B). If acetylcysteine is administered, we suggest giving
1200 mg orally twice daily rather than 600 mg twice daily the day before and the day
of the procedure (Grade 2B). (See 'Acetylcysteine' above.)
•Based upon the lack of convincing evidence of benefit and the potential risk of
anaphylactoid reactions, we suggest not using intravenous acetylcysteine for the
prevention of contrast nephropathy (Grade 2B). (See 'Intravenous therapy' above.)
•We recommend not using mannitol or other diuretics prophylactically (Grade 1B).
(See 'Our approach to fluid administration' above.)
•Among patients with stage 3 and 4 chronic kidney disease (CKD), we
recommend not performing prophylactic hemofiltration or hemodialysis after contrast
exposure (Grade 1B). (See 'Prophylactic hemofiltration and hemodialysis' above.)
•We do not believe there are sufficient data to support the use of prophylactic
hemodialysis following contrast exposure, even among patients with stage 5 CKD
who have a functioning hemoaccess.
Mucolytic agents and airway hydration — A variety of agents, such as nebulized hypertonic
saline solution,mannitol, and mucolytic agents, have been developed to help patients clear their
airways of secretions. Nebulized hypertonic saline and dornase alfa are beneficial in cystic
fibrosis
●Nebulized hypertonic saline – Nebulized hypertonic (6 to 7 percent) saline has been
studied as a mucokinetic therapy [30,31]. The mechanism of action is thought to be related
to improved mucus rheology, increased ciliary motility, and enhanced cough clearance.
Another possibility, suggested by in vitro data, is that low mucus salinity rather than under
hydration contributes to mucus retention, which is counteracted by hypertonic saline [32].
Based on clinical experience, we use hypertonic saline in patients with tenacious or
copious phlegm to augment expectoration.
The efficacy of nebulized hypertonic saline (6 percent) was examined in 40 patients with
noncystic fibrosis bronchiectasis who were randomly assigned to treatments with
hypertonic saline or isotonic saline daily for 12 months [33]. No between group differences
were found in exacerbation rates, quality of life, FEV 1, or sputum colonization.
●Nebulized mannitol – Mannitol is a hyperosmolar agent that is thought to hydrate airway
secretions, which might improve mucus clearance. However, clinical trials have failed to
meet primary efficacy end-points in noncystic fibrosis bronchiectasis, and the available
evidence does not suggest benefit for inhaled mannitol in non-cystic fibrosis
bronchiectasis [31,34,35]. As an example, a multicenter trial (the largest therapeutic trial in
bronchiectasis) randomly assigned 461 patients to inhale dry powder mannitol 400 mg or
mannitol 50 mg (control) twice daily for 52 weeks [34]. The low dose of mannitol was used
as the negative control as it has the same taste and sensation characteristics as the full
dose, but was ineffective in a prior dose-ranging study. The exacerbation rate was not
significantly reduced by mannitol 400 mg (RR 0.92, 95% CI 0.78-1.08). Modest, but
significant improvements were noted in time to first exacerbation (165 versus 124 days for
mannitol and control, respectively, p = 0.021), days of antibiotics to treat exacerbations,
and quality of life by St. George’s Respiratory Questionnaire.
Aerosol dry powder mannitol is not approved for use in bronchiectasis in the United
States. The dry powder formulation of mannitol for bronchoprovocation testing is available
in many countries, but not the United States. While adverse events are not generally more
frequent with mannitol than with placebo, changes in airway osmolarity caused by
mannitol inhalation can lead to mast cell mediator release and bronchoconstriction in
patients with asthma. Thus, mannitol use can only be considered in patients with
bronchiectasis who do not have asthma or have a negative mannitol provocation test.
(See"Bronchoprovocation testing", section on 'Mannitol'.)
●Mucolytic agents – Studies of mucolytic agents have yielded variable results [36]. As an
example,acetylcysteine, a mucolytic agent that cleaves disulfide bonds in glycoproteins,
has not demonstrated clear benefit among patients with cystic fibrosis (CF), and there are
no well-designed studies in non-CF-related bronchiectasis [37].
Aerosolized dornase alpha (recombinant deoxyribonuclease, also called DNase), which
breaks down DNA (a major gelatinous product of neutrophils), improves pulmonary
function (FEV1) and reduces hospitalizations in patients with CF [38], but is not effective in
non-CF-related bronchiectasis and is potentially harmful [39]. (See "Role of mucoactive
agents in the treatment of COPD".)
●Systemic hydration – Maintenance of euvolemia with oral liquids is a logical, although
unstudied, approach to avoiding inspissation of secretions. There is no evidence that
hydration beyond euvolemia provides any benefit.
Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis.
AU
Kellett F, Robert NM
SO
Respir Med. 2011;105(12):1831.
Sputum retention is a distressing feature of non-cystic fibrosis bronchiectasis and has been shown to contribute
to the vicious cycle of infection seen in this disease. In a previous study we demonstrated that nebulised 7%
hypertonic saline was both safe and effective in this patient population. Patients with a clinical diagnosis of noncystic fibrosis bronchiectasis, confirmed by HRCT, were entered into a randomised single blind cross-over study
to evaluate 0.9% sodium chloride (IS) and 7% hypertonic saline (HS). Following a 4 week run in patients
received a random order active HS or IS daily for 3 months. A 4 week wash-out phase was included between
phases. We report lung function, quality of life, and health care utilisation responses. 32 patients mean age 56.6
years (SD 14.6), 16 male, were recruited of which 28 were randomised and completed the study. Lung function
(%change from baseline) improved in HS vs. IS (FEV(1): 15.1, 1.8 p<0.01; FVC: 11.2, 0.7 p<0.01. SGRQ
improved significantly from baseline (HS 6.0, IS 1.2; p<0.05). There were reductions in annualised antibiotic
usage (HS 2.4, IS 5.4 courses per patient per year), annualised emergency health care utilisation visits were
reduced (HS 2.1, IS 4.9 events per patient per year). There were also improvements in sputum viscosity and
ease of expectoration (visual analogue scale). Regular use of 7% hypertonic saline improves lung
function,quality of life and health care utilisation in non-cystic fibrosis bronchiectasis patients.
Inhaled hyperosmolar agents for bronchiectasis.
AU
Hart A, Sugumar K, Milan SJ, Fowler SJ, Crossingham I
SO
Cochrane Database Syst Rev. 2014;5:CD002996.
BACKGROUND: Mucus retention in the lungs is a prominent feature of bronchiectasis. The stagnant mucus
becomes chronically colonised with bacteria, which elicit a host neutrophilic response. This fails to eliminate the
bacteria, and the large concentration of host-derived protease may contribute to the airway damage. The
sensation of retained mucus is itself a cause of suffering, and the failure to maintain airway sterility probably
contributes to the frequent respiratory infections experienced by many patients.Hypertonic saline inhalation is
known to accelerate tracheobronchial clearance in many conditions, probably by inducing a liquid flux into the
airway surface, which alters mucus rheology in a way favourable to mucociliary clearance. Inhaled dry powder
mannitol has a similar effect. Such agents are an attractive approach to the problem of mucostasis, and deserve
further clinical evaluation.
OBJECTIVES: To determine whether inhaled hyperosmolar substances are effective in the treatment of
bronchiectasis.
SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, trials registries, and the
reference lists of included studies and review articles. Searches are current up to April 2014.
SELECTION CRITERIA: Any randomised controlled trial (RCT) using hyperosmolar inhalation in patients with
bronchiectasis not caused by cystic fibrosis.
DATA COLLECTION AND ANALYSIS: Two review authors assessed studies for suitability. We used standard
methods recommended by The Cochrane Collaboration.
MAIN RESULTS: Eleven studies met the inclusion criteria of the review (1021 participants).Five studies on 833
participants compared inhaled mannitol with placebo but poor outcome reporting meant we could pool very little
data and most outcomes were reported by only one study. One 12-month trial on 461 participants provided
results for exacerbations and demonstrated an advantage for mannitol in terms of time to first exacerbation
(median time to exacerbation 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78,
95% confidence interval (CI) 0.63 to 0.96, P = 0.022) and number of days on antibiotics for bronchiectasis
exacerbations was significantly better with mannitol (risk ratio (RR) 0.76, 95%CI 0.58 to 1.00, P = 0.0496).
However, exacerbation rate per year was not significantly different between mannitol and placebo (RR 0.92 95%
CI 0.78 to 1.08). The quality of this evidence was rated as moderate. There was also an indication, from only
three trials, again based on moderate quality evidence, that mannitol improves health-related quality of life (mean
difference (MD) -2.05; 95% CI -3.69 to -0.40). An analysis of adverse events data, also based on moderate
quality evidence, revealed no difference between mannitol and placebo (OR 0.96; 95% CI 0.61 to 1.51). Two
additional small trials on 25 participants compared mannitol versus no treatment and the data from these studies
were inconclusive.Four studies (combined N = 113) compared hypertonic saline versus isotonic saline. On most
outcomes there were conflicting results and the opportunities for the statistical aggregation of data from studies
was very limited. It is not possible to draw robust conclusions for this comparison and judgments should be
reserved until further data are available.
AUTHORS' CONCLUSIONS: There is an indication from a single, large, unpublished study that inhaled mannitol
increases time to first exacerbation in patients with bronchiectasis. In patients with near normal lung function,
spirometry does not change dramatically with mannitol and adverse events are not more frequent than placebo.
Further investigation is required in a patient population with impaired lung function.It is not possible to draw firm
conclusions regarding the effect of nebulised hypertonic saline due to significant differences in the methodology,
patient groups, and findings amongst the limited data available. The data suggest that it is unlikely to have
benefit over isotonic saline in patients with milder disease, and hence future studies should test its use in those
with more severe disease.
The long term effect of inhaled hypertonic saline 6% in non-cystic fibrosis bronchiectasis.
AU
Nicolson CH, Stirling RG, Borg BM, Button BM, Wilson JW, Holland AE
SO
Respir Med. 2012 May;106(5):661-7. Epub 2012 Feb 19.
BACKGROUND AND AIMS: Inhalation of hypertonic saline (HTS) has short term positive effects on airways
clearance in non-cystic fibrosis (CF) bronchiectasis, however its long term effects are unknown. The aim of this
study was to determine the effect of HTS 6% on exacerbations, quality of life (QOL) and respiratory function over
12 months in non-CF bronchiectasis.
METHODS: Forty patients were randomised to inhale isotonic saline (IS) 0.9% or HTS 6% daily for 12 months.
Participants recorded their symptoms in a daily diary. Quality of life and respiratory function were measured after
three, six and 12 months. Number of exacerbations and changes in sputum colonisation were recorded at 12
months. Participants, assessors and clinicians were blinded to group allocation.
RESULTS: The exacerbation rate at 12 months was similar in the two groups and similar clinically significant
improvements in QOL were seen in both groups. The FEV(1) increased in both groups after six months (mean
90 ml, 95% confidence interval 11-169 ml) with no difference between groups (p = 0.394). The FEF(2575%)significantly improved at all time points (mean increase at 12 months 187 ml, 69-304 ml) with no difference
between groups (p = 0.705). There was a reduction in sputum colonisation in both groups (p = 0.046).
CONCLUSIONS: Inhalation of HTS or IS has similar effects on exacerbations, QOL, sputum colonisation and
respiratory function over 12 months in non-CF bronchiectasis. The trial was registered with both Clinical
Trials.gov - NCT00484263 and Australian New Zealand Clinical Trials Registry
nhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial.
AU
Bilton D, Tino G, Barker AF, Chambers DC, De Soyza A, Dupont LJ, O'Dochartaigh C, van Haren EH, Vidal LO,
Welte T, Fox HG, Wu J, Charlton B, B-305 Study Investigators
SO
Thorax. 2014 Dec;69(12):1073-9. Epub 2014 Sep 21.
RATIONALE: Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations.
Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been
conducted.
OBJECTIVES: To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic
fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations,
antibiotic use for exacerbations and quality of life (QOL) (St George's Respiratory Questionnaire, SGRQ).
METHODS: Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and≥2
pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled
mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18-85 years of age, baseline
FEV1≥40% and≤85% predicted and a baseline SGRQ score≥30.
MAIN RESULTS: 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline
demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol
(rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022).
SGRQ score was improved on mannitol compared with low-dose mannitol control (-2.4 units, p=0.046). Adverse
events were similar between groups.
CONCLUSIONS: Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant
bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in
time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated.
Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic
treatment of non-cystic fibrosis bronchiectasis.
AU
Bilton D, Daviskas E, Anderson SD, Kolbe J, King G, Stirling RG, Thompson BR, Milne D, Charlton B
SO
Chest. 2013;144(1):215.
BACKGROUND: Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2
weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate the efficacy and safety of
dry powder mannitol over 12 weeks.
METHODS: Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years,
with FEV1≥50% predicted and≥1 L participated in a randomized, placebo-controlled, double-blind study. Patients
with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n = 231) or placebo (n =
112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient
subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in
24-h sputum weight and St. George's Respiratory Questionnaire (SGRQ) score.
RESULTS: There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95%
CI, 1.64-7.00; P = .002) between mannitol and placebo; however, this was largely driven by a decrease in
sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group
(50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference
between the groups (P = .304) in total SGRQ score (mannitol, -3.4 points [95% CI, -4.81 to -1.94]vs placebo, -2.1
points [95% CI, -4.12 to -0.09]). In a subgroup study (n = 82), patients receiving mannitol showed less small
airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo (P = .048).
Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo.
CONCLUSION: Because the difference in sputum weights appears to be associated with increased antibiotic use
in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on
pulmonary exacerbations and antibiotic use.
Mucolytics for bronchiectasis.
AU
Wilkinson M, Sugumar K, Milan SJ, Hart A, Crockett A, Crossingham I
SO
Cochrane Database Syst Rev. 2014;5:CD001289.
BACKGROUND: Bronchiectasis is predominantly an acquired disease process that represents the end stage of
a variety of unrelated pulmonary insults. It is defined as persistent irreversible dilatation and distortion of
medium-sized bronchi. It has been suggested that with widespread use of high-resolution computed tomography,
more bronchiectasis diagnoses are being made. Patients diagnosed with bronchiectasis frequently have difficulty
expectorating sputum. Sputum therefore is retained in the lungs and may become infected, leading to further
lung damage. Mucolytic agents target hypersecretion or changed physiochemical properties of sputum to make it
easier to clear. One drug, recombinant human DNase, breaks down the DNA that is released at the site of
infection by neutrophils.Mucus clearance along with antimicrobial therapy remains an integral part of
bronchiectasis management. Chest physiotherapy along with mucolytic agents is commonly used in practice
without clear supportive evidence.
OBJECTIVES: To determine whether ingested or inhaled mucolytics are effective in the treatment of patients
with bronchiectasis.
SEARCH METHODS: We searched the Cochrane Airways Group Specialised Registerand reference lists of
relevant articles. We contacted experts in the field and drug companies. Searches were current as of June 2013.
SELECTION CRITERIA: Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic
fibrosis.
DATA COLLECTION AND ANALYSIS: Data extraction was performed independently by two review authors.
Study authors were contacted for confirmation.
MAIN RESULTS: Four trials (with a combined total of 528 adult participants) were included, but almost none of
the data from these studies could be aggregated in a meta-analysis.One trial (with 88 participants) compared
bromhexine versus placebo. Compared with placebo, high doses of bromhexine with antibiotics eased difficulty
in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the quality
of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%,
95% CI -38.9 to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences
between bromhexine and placebo were observed with respect to reported adverse events (odds ratio (OR) 2.93;
95% CI 0.12 to 73.97), and again the quality of the evidence was rated as low.In a single small, blinded but not
placebo-controlled trial of older (>55 years) participants with stable bronchiectasis and mucus hypersecretion,
erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more
effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced
expiratory volume in one second (FEV1) and 300 mL in forced vital capacity (FVC)) and was apparent only at
day 15, not at earlier time points.The remaining two studies (with a combined total of 410 participants) compared
recombinant human DNase (RhDNase) versus placebo. These two studies were very different (one was a twoweek study of 61 participants, and the other ran for 24 weeks and included 349 participants), and the opportunity
for combining data from the two studies was very limited. Compared with placebo, recombinant human DNase
showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on FEV1 in
the larger and longer study. For reported adverse events, no significant differences between recombinant human
DNase and placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo,
the quality of the evidence was judged to be low.
AUTHORS' CONCLUSIONS: Given the harmful effects of recombinant human DNase in one trial and no
evidence of benefit, this drug should be avoided in non-cystic fibrosis bronchiectasis, except in the context of
clinical trials. Evidence is insufficient to permit evaluation of the routine use of other mucolytics for
bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and
clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful
adjunct to physiotherapy in stable patients with mucus hypersecretion, but robust longer-term trials are
required.Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of
agents available on the market, such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement
of the evidence base is needed.