Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Feeling as though they play an active role in their treatment decisions increases satisfaction among cancer patients undergoing radiotherapy (RT), according to research published in Cancer.

In a study of more than 300 RT patients, those who were involved in their treatment decisions—or perceived they had some control over their treatment—were more satisfied than their peers.

On the other hand, patients who wanted control over their treatment but did not feel they had any were more likely than their peers to experience anxiety, depression, and fatigue.

“Our findings emphasize the value of patient-physician relationships and communication, specifically in radiation oncology, and their impact on patient experience in a way that hasn’t been shown before,” said study author Neha Vapiwala, MD, of the Perelman School of Medicine at the University of Pennsylvania.

Dr Vapiwala and her colleagues noted that past studies of shared decision-making (SDM)—in which patients and providers make healthcare decisions together, taking into account scientific evidence and patient preferences—have shown an association between patient satisfaction and quality of life.

However, none of these studies has evaluated the impact of SDM on patients undergoing RT. Often, radiation oncology is seen as a treatment avenue that is ultimately left to the physician to dictate. But there are tailored options, decisions, and discussions that can apply to individual patients.

With this in mind, the researchers conducted a survey of SDM in 305 patients undergoing RT. In all, 31% of patients said they experienced SDM, 32% perceived control in their treatment decisions, and 76% reported feeling very satisfied with their radiation treatment course overall.

Patient satisfaction was significantly higher among those who perceived SDM than among those who did not—84.4% and 71.4%, respectively (P<0.02).

And satisfaction was higher among patients who perceived control over their treatment than among those who did not—89.7% and 69.2%, respectively (P<0.001).

Patients who expressed a desire for control over their treatment decisions but did not perceive having any control were significantly more likely than their peers to experience symptoms tied to psychological distress.

Anxiety was reported in 44% and 20% of patients, respectively (P<0.02). Depression was reported in 44% and 15%, respectively (P<0.01). And fatigue was reported in 68% and 39.2%, respectively (P<0.01).

The researchers said one of this study’s strengths is the diverse group of patients enrolled. Ages ranged from 18 to 87 years, and a variety of ethnic/racial groups were represented. Patients had a range of cancers at all stages, and could participate in the study as long as they were well enough.

The team said the next step for this research is to determine both physician and patient barriers to SDM and identify methods to break down these barriers.

“As providers, it doesn’t matter what treatment you are offering, or how complicated it is, or how busy you may be,” Dr Vapiwala said. “It’s worth taking even a few minutes to talk to patients about seemingly minor decisions in which they can provide some input.”

“It’s not only critical in today’s healthcare setting, where both information and misinformation are rampant, but will very likely lead to the patient feeling positively about the encounter.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Feeling as though they play an active role in their treatment decisions increases satisfaction among cancer patients undergoing radiotherapy (RT), according to research published in Cancer.

In a study of more than 300 RT patients, those who were involved in their treatment decisions—or perceived they had some control over their treatment—were more satisfied than their peers.

On the other hand, patients who wanted control over their treatment but did not feel they had any were more likely than their peers to experience anxiety, depression, and fatigue.

“Our findings emphasize the value of patient-physician relationships and communication, specifically in radiation oncology, and their impact on patient experience in a way that hasn’t been shown before,” said study author Neha Vapiwala, MD, of the Perelman School of Medicine at the University of Pennsylvania.

Dr Vapiwala and her colleagues noted that past studies of shared decision-making (SDM)—in which patients and providers make healthcare decisions together, taking into account scientific evidence and patient preferences—have shown an association between patient satisfaction and quality of life.

However, none of these studies has evaluated the impact of SDM on patients undergoing RT. Often, radiation oncology is seen as a treatment avenue that is ultimately left to the physician to dictate. But there are tailored options, decisions, and discussions that can apply to individual patients.

With this in mind, the researchers conducted a survey of SDM in 305 patients undergoing RT. In all, 31% of patients said they experienced SDM, 32% perceived control in their treatment decisions, and 76% reported feeling very satisfied with their radiation treatment course overall.

Patient satisfaction was significantly higher among those who perceived SDM than among those who did not—84.4% and 71.4%, respectively (P<0.02).

And satisfaction was higher among patients who perceived control over their treatment than among those who did not—89.7% and 69.2%, respectively (P<0.001).

Patients who expressed a desire for control over their treatment decisions but did not perceive having any control were significantly more likely than their peers to experience symptoms tied to psychological distress.

Anxiety was reported in 44% and 20% of patients, respectively (P<0.02). Depression was reported in 44% and 15%, respectively (P<0.01). And fatigue was reported in 68% and 39.2%, respectively (P<0.01).

The researchers said one of this study’s strengths is the diverse group of patients enrolled. Ages ranged from 18 to 87 years, and a variety of ethnic/racial groups were represented. Patients had a range of cancers at all stages, and could participate in the study as long as they were well enough.

The team said the next step for this research is to determine both physician and patient barriers to SDM and identify methods to break down these barriers.

“As providers, it doesn’t matter what treatment you are offering, or how complicated it is, or how busy you may be,” Dr Vapiwala said. “It’s worth taking even a few minutes to talk to patients about seemingly minor decisions in which they can provide some input.”

“It’s not only critical in today’s healthcare setting, where both information and misinformation are rampant, but will very likely lead to the patient feeling positively about the encounter.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Feeling as though they play an active role in their treatment decisions increases satisfaction among cancer patients undergoing radiotherapy (RT), according to research published in Cancer.

In a study of more than 300 RT patients, those who were involved in their treatment decisions—or perceived they had some control over their treatment—were more satisfied than their peers.

On the other hand, patients who wanted control over their treatment but did not feel they had any were more likely than their peers to experience anxiety, depression, and fatigue.

“Our findings emphasize the value of patient-physician relationships and communication, specifically in radiation oncology, and their impact on patient experience in a way that hasn’t been shown before,” said study author Neha Vapiwala, MD, of the Perelman School of Medicine at the University of Pennsylvania.

Dr Vapiwala and her colleagues noted that past studies of shared decision-making (SDM)—in which patients and providers make healthcare decisions together, taking into account scientific evidence and patient preferences—have shown an association between patient satisfaction and quality of life.

However, none of these studies has evaluated the impact of SDM on patients undergoing RT. Often, radiation oncology is seen as a treatment avenue that is ultimately left to the physician to dictate. But there are tailored options, decisions, and discussions that can apply to individual patients.

With this in mind, the researchers conducted a survey of SDM in 305 patients undergoing RT. In all, 31% of patients said they experienced SDM, 32% perceived control in their treatment decisions, and 76% reported feeling very satisfied with their radiation treatment course overall.

Patient satisfaction was significantly higher among those who perceived SDM than among those who did not—84.4% and 71.4%, respectively (P<0.02).

And satisfaction was higher among patients who perceived control over their treatment than among those who did not—89.7% and 69.2%, respectively (P<0.001).

Patients who expressed a desire for control over their treatment decisions but did not perceive having any control were significantly more likely than their peers to experience symptoms tied to psychological distress.

Anxiety was reported in 44% and 20% of patients, respectively (P<0.02). Depression was reported in 44% and 15%, respectively (P<0.01). And fatigue was reported in 68% and 39.2%, respectively (P<0.01).

The researchers said one of this study’s strengths is the diverse group of patients enrolled. Ages ranged from 18 to 87 years, and a variety of ethnic/racial groups were represented. Patients had a range of cancers at all stages, and could participate in the study as long as they were well enough.

The team said the next step for this research is to determine both physician and patient barriers to SDM and identify methods to break down these barriers.

“As providers, it doesn’t matter what treatment you are offering, or how complicated it is, or how busy you may be,” Dr Vapiwala said. “It’s worth taking even a few minutes to talk to patients about seemingly minor decisions in which they can provide some input.”

“It’s not only critical in today’s healthcare setting, where both information and misinformation are rampant, but will very likely lead to the patient feeling positively about the encounter.”

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Changing the administration of chloroquine might prevent resistance to the antimalarial agent, according to a study published in PNAS.

Investigators found the parasite protein that causes chloroquine resistance—the Plasmodium falciparum chloroquine resistance transporter (PfCRT)—has an Achilles’ heel.

“We studied diverse versions of this protein and, in all cases, found that it is limited in its capacity to remove the drug from the parasite,” said Rowena Martin, PhD, of The Australian National University in Canberra.

“This means malaria could once again be treated with chloroquine if it is administered twice-daily, rather than just once a day.”

Dr Martin and her colleagues noted that a number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to chloroquine resistance.

So they set out to characterize these forms of PfCRT and determine the number of mutations, as well as the order of their addition, required to confer chloroquine transport activity.

The investigators analyzed more than 100 variants of PfCRT, measuring their ability to transport chloroquine.

The team identified multiple mutational pathways that led to chloroquine transport via PfCRT but divided these pathways into 2 main lineages.

“We found that the protein gains the ability to move chloroquine out of the parasite through 1 of 2 evolutionary pathways but that this process is rigid,” Dr Martin said. “One wrong turn, and the protein is rendered useless.”

In fact, the investigators found that, if mutations did not occur in a precise order, chloroquine transport activity decreased.

The number of mutations played a key role as well. A minimum of 2 mutations was sufficient for chloroquine transport activity, but as few as 4 conferred full activity.

“This indicates that the protein is under conflicting pressures, which is a weakness that could be exploited in future antimalarial strategies,” Dr Martin said.

She also noted that these findings might not apply only to chloroquine. They might apply to several chloroquine-like drugs that are also becoming less effective as the malaria parasite builds up resistance.

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Changing the administration of chloroquine might prevent resistance to the antimalarial agent, according to a study published in PNAS.

Investigators found the parasite protein that causes chloroquine resistance—the Plasmodium falciparum chloroquine resistance transporter (PfCRT)—has an Achilles’ heel.

“We studied diverse versions of this protein and, in all cases, found that it is limited in its capacity to remove the drug from the parasite,” said Rowena Martin, PhD, of The Australian National University in Canberra.

“This means malaria could once again be treated with chloroquine if it is administered twice-daily, rather than just once a day.”

Dr Martin and her colleagues noted that a number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to chloroquine resistance.

So they set out to characterize these forms of PfCRT and determine the number of mutations, as well as the order of their addition, required to confer chloroquine transport activity.

The investigators analyzed more than 100 variants of PfCRT, measuring their ability to transport chloroquine.

The team identified multiple mutational pathways that led to chloroquine transport via PfCRT but divided these pathways into 2 main lineages.

“We found that the protein gains the ability to move chloroquine out of the parasite through 1 of 2 evolutionary pathways but that this process is rigid,” Dr Martin said. “One wrong turn, and the protein is rendered useless.”

In fact, the investigators found that, if mutations did not occur in a precise order, chloroquine transport activity decreased.

The number of mutations played a key role as well. A minimum of 2 mutations was sufficient for chloroquine transport activity, but as few as 4 conferred full activity.

“This indicates that the protein is under conflicting pressures, which is a weakness that could be exploited in future antimalarial strategies,” Dr Martin said.

She also noted that these findings might not apply only to chloroquine. They might apply to several chloroquine-like drugs that are also becoming less effective as the malaria parasite builds up resistance.

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Changing the administration of chloroquine might prevent resistance to the antimalarial agent, according to a study published in PNAS.

Investigators found the parasite protein that causes chloroquine resistance—the Plasmodium falciparum chloroquine resistance transporter (PfCRT)—has an Achilles’ heel.

“We studied diverse versions of this protein and, in all cases, found that it is limited in its capacity to remove the drug from the parasite,” said Rowena Martin, PhD, of The Australian National University in Canberra.

“This means malaria could once again be treated with chloroquine if it is administered twice-daily, rather than just once a day.”

Dr Martin and her colleagues noted that a number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to chloroquine resistance.

So they set out to characterize these forms of PfCRT and determine the number of mutations, as well as the order of their addition, required to confer chloroquine transport activity.

The investigators analyzed more than 100 variants of PfCRT, measuring their ability to transport chloroquine.

The team identified multiple mutational pathways that led to chloroquine transport via PfCRT but divided these pathways into 2 main lineages.

“We found that the protein gains the ability to move chloroquine out of the parasite through 1 of 2 evolutionary pathways but that this process is rigid,” Dr Martin said. “One wrong turn, and the protein is rendered useless.”

In fact, the investigators found that, if mutations did not occur in a precise order, chloroquine transport activity decreased.

The number of mutations played a key role as well. A minimum of 2 mutations was sufficient for chloroquine transport activity, but as few as 4 conferred full activity.

“This indicates that the protein is under conflicting pressures, which is a weakness that could be exploited in future antimalarial strategies,” Dr Martin said.

She also noted that these findings might not apply only to chloroquine. They might apply to several chloroquine-like drugs that are also becoming less effective as the malaria parasite builds up resistance.

From the Massachusetts General Hospital Center for Pain Medicine, Boston, MA.

Abstract

• Objective: To review evidence from clinical and preclinical studies related to the phenomenon of opioid-induced hyperalgesia (OIH) and discuss issues relevant to clinical diagnosis and management.
• Methods: Literature review.
• Results: OIH is defined as a state of nociceptive sensitization caused by exposure to opioids such that a patient receiving opioids to treat pain could become more sensitive to painful stimuli. Interest in understanding OIH has grown over years and multiple mechanisms have been proposed. Both OIH and opioid tolerance can reduce opioid analgesic efficacy, complicating clinical management of chronic pain. When a diagnosis is uncertain, a trial of opioid dose escalation or tapering may be helpful in differentiating between tolerance and OIH. It is unclear whether certain types of opioids or routes of administration are more likely to lead to OIH.
• Conclusion: Clinical outcome of opioid therapy is a dynamic balance among the opioid analgesic effect, OIH, and worsening pain due to disease progression. While OIH has been well documented over nearly 2 decades, its exact clinical characteristics and underlying mechanisms have yet to be fully determined.

Opioids, which produce analgesia through a primarily inhibitory effect on the nociceptive system, have been used for decades for the clinical management of moderate to severe pain. Opioid analgesics act on 3 major classes of opioid receptors, including the µ, k, δ (mu, kappa, and delta) receptors. Activation of opioid receptors not only produces analgesia but also other effects, such as euphoria, respiratory depression, decreased gastrointestinal motility, and cardiovascular effects. Exposure to opioids, however, can also lead to the development of opioid tolerance and opioid-induced hyperalgesia (OIH). Both opioid tolerance and OIH can decrease opioid analgesic efficacy, making chronic pain management a challenge. OIH is a state of nociceptive sensitization caused by exposure to opioids, such that a patient receiving opioids for the treatment of pain could actually become more sensitive to painful stimulation, resulting in a paradoxical adverse response to opioid therapy. In this article, we will review evidence from preclinical and clinical studies and discuss issues relevant to clinical diagnosis and management of OIH.

Evidence of OIH in Animal Studies

In early 1990s, an original preclinical study showed that there was a progressive reduction in baseline nociceptive threshold by using a foot withdraw test in rats receiving repeated intrathecal morphine administration (10-20 mg) over a 7-day period [1]. A number of animal studies later also provided similar data. A reduced baseline nociceptive threshold was observed in animals receiving subcutaneous fentanyl boluses using the Randall-Sellitto test, in which a constantly increasing pressure was applied to a rat’s hind paw. The decreased baseline nociceptive threshold lasted 5 days after cessation of 4 fentanyl bolus injections [2]. In another study, a reduced baseline nociceptive threshold was detected in animals with repeated heroin administration [3]. In other studies, rats exposed to morphine also developed a latent sensitization of visceral pain with a shift of the morphine dose-response curve to the right [4]; exposure to methadone also induced hyperalgesia in rats, which was not prevented by a weak NMDA receptor antagonist (memantine) [5]; and a partial µ-receptor agonist buprenophine produced a dose-related OIH as well [6].

These results indicate that a progressive and lasting reduction of baseline nociceptive threshold, which was referred to as OIH, can result from repeated opioid administration [7–9]. However, different from previous preclinical observations in which a large dose of intrathecal morphine was given, these studies resulted in hyperalgesic response [10,11] in a clinically relevant opioid dose. Of interest is that OIH was observed in animals even when there was continuous opioid infusion via an implanted osmotic pump, suggesting the involvement of active cellular mechanisms in the process [12]. Therefore, prolonged opioid treatment results in not only loss of the opioid analgesic effect (anti-nociceptive effect or desensitization) but also activation of a hyperalgesic effect (a pro-nociceptive effect with reduced nociceptive threshold or increased sensitization). Although both opioid tolerance and OIH are initiated by opioid administration, two opposing cellular mechanisms (ie, desensitization versus sensitization) may be involved in the process. Subsequently, many studies explored the neural and cellular mechanisms underlying the development of OIH and their interaction with the mechanism of opioid tolerance.

Proposed Cellular Mechanisms of OIH

A significant number of recent studies have explored the neurobiological basis of OIH, revealing a divergent range of cellular elements contributory to OIH. These mechanisms include (1) N-methyl-D-aspartate (NMDA) receptor and related intracellular pathways; (2) involvement of G-protein coupled receptors including 5-HT receptors and neurokinin-1 receptors; (3) nitrix oxide and nitric oxide sunthase; (4) TRPV1 receptors; (5) calcium channels; and (6) miscellaneous mechanisms including sex differences [7–9,13–41].

In summary, an increasing number of preclinical studies in the area of OIH indicates that there is enormous interest in understanding the cellular mechanisms of OIH, and the current evidence points to a progressive sensitization process within the central nervous system that involves a constellation of cellular elements such as NMDA receptors, similar to those contributory to the mechanisms of pathological pain.

Evidence of OIH in Human Studies

In animal studies, changes in baseline nociceptive thresholds can be measured in a controlled setting. It is, however, difficult to assess changes in pain threshold in clinical environment following opioid administration [9]. It is often a challenge to distinguish opioid pharmacologic tolerance from OIH because the outcome of opioid therapy is based primarily on subjective pain scores. In the face of these challenges, an increasing number of clinical anecdotal case reports and studies suggest that OIH is likely to be a significant factor in clinical opioid therapy [47–54].

In a study of 1620 patients in which remifentanil was used for general anesthesia, the incidence of postoperative remifentanil-induced hyperalgesia was 16.1%. This study found that age younger than 16 years, male sex, operation duration longer than 2 hours, and remifentanil dose greater than 30 mg/kga were associated with higher rates of OIH [55]. On the other hand, heroin or other opioid addicts not only demonstrated OIH but also had prolonged symptoms of OIH after detoxification from opioids for at least 1 month [56]. In chronic pain patients without opioid dependence, significantly lower pain threshold and tolerance as assessed by pressure pain stimulation were detected [57]. It appears that the sensitivity of detecting OIH in the clinical setting may be influenced by the modality of sensory stimulation [58].

In a prospective preliminary study of 6 patients with chronic low back pain, hyperalgesic response was detected after 1 month of oral morphine therapy using a cold pressor test but not a heat pain test [59]. In another prospective randomized, placebo-controlled, 2-way crossover study in healthy human volunteers, the development of OIH was quantified as changes in the average radius of the area of secondary hyperalgesia generated by electrical pain stimulation. A 23.6% increase in the area of secondary hyperalgesia over baseline was detected following the remifentanil infusion. The same study showed that endogenous opioids did not seem to have an effect on OIH because a single bolus of naloxone did not change the size of secondary hyperalgesia [60].

OIH Prevention Studies

Currently, efforts have also been made to see whether OIH can be prevented with different approaches in human subjects. The following is a brief summary of these studies. In a study of adolescents undergoing scoliosis surgery, treatment with morphine (150 mg/kg) prior to commencing remifentanil infusion did not prevent the development of remifentanil-induced hyperalgesia [61]. In another study, propofol infusion alone with remifentanil both delayed and attenuated remifentanil-induced hyperalgesia [53]. In yet another study, intraoperative 70% N2O administration appeared to reduce postoperative OIH following an intraoperative remifentanil-propofol anesthesia regimen [62].

In a study of 15 healthy male volunteers, preventive administration of parecoxib significantly diminished OIH after withdrawal from remifentanil. In contrast, parecoxib given together with remifentanil did not prevent OIH, suggesting that pre-treatment, not parallel treatment, with opioid may be required to prevent OIH [63]. Other NSAIDs administered preemptively also appear to prevent remifentanil-induced hyperalgesia [64].

Another study investigated the effect of intra-operative magnesium sulfate administration in patients undergoing robot-assisted laparoscopic prostatectomy. Magnesium sulfate administration reduced postoperative opioid consumption and OIH in subjects receiving intra-operative remifentanil-based anesthesia [65,66]. Intra-operative adenosine infusion also prevented acute opioid tolerance and remifentanil-induced hyperalgesia [67]. Continuous intra-operative infusion of ketamine, an NMDA receptor antagonist, significant lowered postoperative VAS and morphine use in gynecologic surgery patients [68]. Also, in a randomized, double-blind, placebo-controlled study of 90 patients who underwent total abdominal hysterectomy, cumulative morphine consumption was significantly greater in subjects with fentanyl alone than those with saline alone, ketamine alone, ketamine with fentanyl, or fentanyl with lornoxicam at 3, 6, and 12 hours postoperatively [69].

Finally, in a double-blind, randomized, placebo-controlled study of 40 patients undergoing elective shoulder surgery, clonidine was given intra-operatively in a remifentanil/propofol-based anesthesia. The results showed that clonidine did not reduce postoperative morphine consumption and pain score in these patients [70]. However, dexmedetomidine, another α2 receptor agonist, substantially reduced baseline opioid doses in hospitalized patients with OIH [71].

Quantitative Sensory Testing and OIH

Currently, diagnostic tools for OIH are still being developed. Many clinical studies have used quantitative sensory testing (QST) as a tool to assess OIH [72,73]. In a recent study, QST was used to compare pain threshold, pain tolerance, and the degree of temporal summation of pain in response to thermal stimulation among 3 groups of subjects: Group 1 (no pain and no opioid), Group 2 (chronic pain but no opioid therapy), and Group 3 (both chronic pain and opioid therapy). Group 3 subjects displayed a decreased heat pain threshold and exacerbated temporal summation of pain to thermal stimulation as compared with both group 1 and group 2 subjects. There were no differences in cold or warm sensation among all 3 groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of second pain in group 3 subjects [72]. Another study investigated the sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) using QST in subjects with or without opioid therapy. Pain threshold, intensity and tolerance in response to the cold pressor (1°C) were measured. They found that oral opioid use did not result in abnormal sensitivity to cold pain but altered pain modulation as detected by DNIC [74].

Opioid Regimen and OIH

Opioid regimen features, including type of opioid and dose, may influence the development of OIH. Anecdotal clinical observations have suggested that degree of OIH may vary according to opioid regimen [75]. Although the exact relationship between the dose regimen and the development of OIH remains to be determined, it is conceivable that OIH would be more likely to develop in patients receiving high opioid doses with a prolonged treatment course, although OIH has been demonstrated in patients receiving a short course of highly potent opioid analgesics [76]. Moreover, patients with a pathological pain condition (eg, neuropathic pain) treated with opioid therapy may be more susceptible to developing opioid-induced pain, because both pathological pain and OIH may share a common cellular mechanism [77].

If OIH develops following exposure to one opioid, can switching to a different opioid diminish OIH [78]?If cross-pain sensitivity does not develop between different opioids, switching to a different opioid would be justified, a similar rationale to that for opioid rotation to overcome opioid tolerance. This issue remains to be addressed.

OIH and Pre-emptive Analgesia

There is an ongoing debate about the clinical effectiveness of pre-emptive analgesia in pain management. However, use of opioid analgesic as the sole agent for pre-emptive analgesia may not be desirable for several reasons. First, a large dose of intra-operative opioids could activate a pro-nociceptive mechanism leading to the development of postoperative OIH [79]. This may confound the assessment of postoperative pain and counteract the opioid analgesic effect. Second, pre-emptive analgesia calls for pre-emptive inhibition of neuroplastic changes mediated through multiple cellular mechanisms such as the central glutamatergic system. Paradoxically, opioid administration could activate the central glutamatergic system as discussed above. Third, the neural mechanism of opioid tolerance and OIH may interact with that of pathological pain and pathological pain could be exacerbated following opioid administration [80,81]. This issue needs to be investigated in future studies.

Clinical Implications and Management of OIH

Until recently, a decreased opioid analgesic effect associated with opioid therapy was often recognized as the presence of pharmacologic opioid tolerance (ie, desensitization of the responsiveness of the opioid receptor and its cellular mechanism) and/or a worsening of the clinical pain condition. Therefore, opioid dose escalation appeared to be a logical approach to regain analgesic effectiveness. This practice should be reconsidered in light of the information on OIH. In the clinical setting, apparent opioid tolerance may result from pharmacological tolerance, worsening pain condition due to disease progression, and/or OIH. Below are some factors to consider in forming a differential diagnosis in the clinical setting [82].

First, the quality, location, and distribution pattern of the pain related to OIH would be different from a pre-existing pain condition. Because opioid analgesics are often administered systemically, changes in pain quality would be diffuse as compared with the pre-existing pain condition. Since the mechanism of OIH is similar to that of pathological pain, such as neuropathic pain, changes in pain threshold, tolerability, and distribution patterns seen in OIH would be similar to those seen in neuropathic pain patients. Quantitative sensory testing may be a useful tool to detect such changes.

Second, OIH would possibly exacerbate a pre-existing pain condition. Overall pain intensity (VAS) would be conceivably increased above the level of pre-existing pain in the absence of disease progression. Opioid dose escalation could only transiently and minimally reduce pain intensity in such a setting, with a subsequent increase in pain intensity due to OIH.

Third, when a diagnosis is uncertain, a trial of opioid dose escalation or tapering may be helpful to differentiate between tolerance and OIH. In an undertreated, worsening pain condition due to disease progress and/or pharma-cologic opioid tolerance, improved pain control may well be seen after a trial of opioid dose escalation. On the other hand, opioid dose escalation may exacerbate pain due to OIH, while a supervised opioid tapering may reduce OIH and improve clinical pain management. In this regard, if a patient is on a low opioid dose regimen and complains of unsatisfactory pain relief, a trial of opioid dose escalation may be appropriate; if a patient is already on a high dose of opioid analgesics, further dose escalation is rarely justified and may exacerbate OIH.

It is important to remember that the clinical outcome of opioid therapy is a dynamic balance among the opioid analgesic effect, OIH, and worsening pain due to disease progression. While any opioid dose escalation may transiently increase the analgesic effect, albeit by a small degree in many cases, the real issue is whether the same dose escalation may also exacerbate OIH, which could quickly overtake the transient increase in the opioid analgesic effect. Therefore, clinical judgment is fundamentally important and all clinical conditions related to opioid therapy need to be taken into consideration in the decision making process.

Summary

Interest in understanding OIH has grown over the last decade. Many discussions and reviews have centered around several key issues: (1) opioids not only produce analgesia through their anti-nociceptive effect, but also induce hyperalgesia via a pro-nociceptive effect; (2) opioid tolerance itself may be part of sensitization of a pro-nociceptive process; (3) the onset of OIH may be later than that of opioid tolerance and OIH may be a dose-related process, although OIH has been reported following acute and chronic opioid exposure at both high and low doses; (4) it is unclear whether a certain type of opioid and route of administration may be more likely to lead to clinical presentation of OIH; and (5) although opioid tolerance, OIH, and opioid withdrawal may share some common factors and mechanisms, the mechanism underlying each of these phenomena remains unclear [83].

While OIH has been well documented and investigated over nearly 2 decades, its exact clinical characteristics and underlying mechanisms have yet to be fully determined [84]. In addition, opioid tolerance should be differentiated from OIH, although both have a similar clinical presentation with regard to change in pain intensity [85]. Clinically, OIH should be considered when the adjustment of opioid dose is contemplated if prior opioid dose escalation fails to provide the expected analgesic effect and there is unexplainable pain exacerbation following an initial period of effective opioid analgesia. Although in some cases increasing opioid dose leads to some improvement in pain management, in other cases less opioid may be more effective in pain reduction. This goal may be accomplished by initiating a trial of opioid tapering, opioid rotation, adding adjunctive medications, or combining opioid with a clinically available NMDA receptor antagonist. Continuing opioid therapy with endless dose escalation in the absence of clinical evidence of improved pain management is neither scientifically sound nor clinically justified.

Corresponding author: Lucy L. Chen, MD, MGH Center for Pain Medicine, WACC #340, 15 Parkman St., Boston, MA 02114.

Financial disclosures: None.

From the Massachusetts General Hospital Center for Pain Medicine, Boston, MA.

Abstract

• Objective: To review evidence from clinical and preclinical studies related to the phenomenon of opioid-induced hyperalgesia (OIH) and discuss issues relevant to clinical diagnosis and management.
• Methods: Literature review.
• Results: OIH is defined as a state of nociceptive sensitization caused by exposure to opioids such that a patient receiving opioids to treat pain could become more sensitive to painful stimuli. Interest in understanding OIH has grown over years and multiple mechanisms have been proposed. Both OIH and opioid tolerance can reduce opioid analgesic efficacy, complicating clinical management of chronic pain. When a diagnosis is uncertain, a trial of opioid dose escalation or tapering may be helpful in differentiating between tolerance and OIH. It is unclear whether certain types of opioids or routes of administration are more likely to lead to OIH.
• Conclusion: Clinical outcome of opioid therapy is a dynamic balance among the opioid analgesic effect, OIH, and worsening pain due to disease progression. While OIH has been well documented over nearly 2 decades, its exact clinical characteristics and underlying mechanisms have yet to be fully determined.

Opioids, which produce analgesia through a primarily inhibitory effect on the nociceptive system, have been used for decades for the clinical management of moderate to severe pain. Opioid analgesics act on 3 major classes of opioid receptors, including the µ, k, δ (mu, kappa, and delta) receptors. Activation of opioid receptors not only produces analgesia but also other effects, such as euphoria, respiratory depression, decreased gastrointestinal motility, and cardiovascular effects. Exposure to opioids, however, can also lead to the development of opioid tolerance and opioid-induced hyperalgesia (OIH). Both opioid tolerance and OIH can decrease opioid analgesic efficacy, making chronic pain management a challenge. OIH is a state of nociceptive sensitization caused by exposure to opioids, such that a patient receiving opioids for the treatment of pain could actually become more sensitive to painful stimulation, resulting in a paradoxical adverse response to opioid therapy. In this article, we will review evidence from preclinical and clinical studies and discuss issues relevant to clinical diagnosis and management of OIH.

Evidence of OIH in Animal Studies

In early 1990s, an original preclinical study showed that there was a progressive reduction in baseline nociceptive threshold by using a foot withdraw test in rats receiving repeated intrathecal morphine administration (10-20 mg) over a 7-day period [1]. A number of animal studies later also provided similar data. A reduced baseline nociceptive threshold was observed in animals receiving subcutaneous fentanyl boluses using the Randall-Sellitto test, in which a constantly increasing pressure was applied to a rat’s hind paw. The decreased baseline nociceptive threshold lasted 5 days after cessation of 4 fentanyl bolus injections [2]. In another study, a reduced baseline nociceptive threshold was detected in animals with repeated heroin administration [3]. In other studies, rats exposed to morphine also developed a latent sensitization of visceral pain with a shift of the morphine dose-response curve to the right [4]; exposure to methadone also induced hyperalgesia in rats, which was not prevented by a weak NMDA receptor antagonist (memantine) [5]; and a partial µ-receptor agonist buprenophine produced a dose-related OIH as well [6].

These results indicate that a progressive and lasting reduction of baseline nociceptive threshold, which was referred to as OIH, can result from repeated opioid administration [7–9]. However, different from previous preclinical observations in which a large dose of intrathecal morphine was given, these studies resulted in hyperalgesic response [10,11] in a clinically relevant opioid dose. Of interest is that OIH was observed in animals even when there was continuous opioid infusion via an implanted osmotic pump, suggesting the involvement of active cellular mechanisms in the process [12]. Therefore, prolonged opioid treatment results in not only loss of the opioid analgesic effect (anti-nociceptive effect or desensitization) but also activation of a hyperalgesic effect (a pro-nociceptive effect with reduced nociceptive threshold or increased sensitization). Although both opioid tolerance and OIH are initiated by opioid administration, two opposing cellular mechanisms (ie, desensitization versus sensitization) may be involved in the process. Subsequently, many studies explored the neural and cellular mechanisms underlying the development of OIH and their interaction with the mechanism of opioid tolerance.

Proposed Cellular Mechanisms of OIH

A significant number of recent studies have explored the neurobiological basis of OIH, revealing a divergent range of cellular elements contributory to OIH. These mechanisms include (1) N-methyl-D-aspartate (NMDA) receptor and related intracellular pathways; (2) involvement of G-protein coupled receptors including 5-HT receptors and neurokinin-1 receptors; (3) nitrix oxide and nitric oxide sunthase; (4) TRPV1 receptors; (5) calcium channels; and (6) miscellaneous mechanisms including sex differences [7–9,13–41].

In summary, an increasing number of preclinical studies in the area of OIH indicates that there is enormous interest in understanding the cellular mechanisms of OIH, and the current evidence points to a progressive sensitization process within the central nervous system that involves a constellation of cellular elements such as NMDA receptors, similar to those contributory to the mechanisms of pathological pain.

Evidence of OIH in Human Studies

In animal studies, changes in baseline nociceptive thresholds can be measured in a controlled setting. It is, however, difficult to assess changes in pain threshold in clinical environment following opioid administration [9]. It is often a challenge to distinguish opioid pharmacologic tolerance from OIH because the outcome of opioid therapy is based primarily on subjective pain scores. In the face of these challenges, an increasing number of clinical anecdotal case reports and studies suggest that OIH is likely to be a significant factor in clinical opioid therapy [47–54].

In a study of 1620 patients in which remifentanil was used for general anesthesia, the incidence of postoperative remifentanil-induced hyperalgesia was 16.1%. This study found that age younger than 16 years, male sex, operation duration longer than 2 hours, and remifentanil dose greater than 30 mg/kga were associated with higher rates of OIH [55]. On the other hand, heroin or other opioid addicts not only demonstrated OIH but also had prolonged symptoms of OIH after detoxification from opioids for at least 1 month [56]. In chronic pain patients without opioid dependence, significantly lower pain threshold and tolerance as assessed by pressure pain stimulation were detected [57]. It appears that the sensitivity of detecting OIH in the clinical setting may be influenced by the modality of sensory stimulation [58].

In a prospective preliminary study of 6 patients with chronic low back pain, hyperalgesic response was detected after 1 month of oral morphine therapy using a cold pressor test but not a heat pain test [59]. In another prospective randomized, placebo-controlled, 2-way crossover study in healthy human volunteers, the development of OIH was quantified as changes in the average radius of the area of secondary hyperalgesia generated by electrical pain stimulation. A 23.6% increase in the area of secondary hyperalgesia over baseline was detected following the remifentanil infusion. The same study showed that endogenous opioids did not seem to have an effect on OIH because a single bolus of naloxone did not change the size of secondary hyperalgesia [60].

OIH Prevention Studies

Currently, efforts have also been made to see whether OIH can be prevented with different approaches in human subjects. The following is a brief summary of these studies. In a study of adolescents undergoing scoliosis surgery, treatment with morphine (150 mg/kg) prior to commencing remifentanil infusion did not prevent the development of remifentanil-induced hyperalgesia [61]. In another study, propofol infusion alone with remifentanil both delayed and attenuated remifentanil-induced hyperalgesia [53]. In yet another study, intraoperative 70% N2O administration appeared to reduce postoperative OIH following an intraoperative remifentanil-propofol anesthesia regimen [62].

In a study of 15 healthy male volunteers, preventive administration of parecoxib significantly diminished OIH after withdrawal from remifentanil. In contrast, parecoxib given together with remifentanil did not prevent OIH, suggesting that pre-treatment, not parallel treatment, with opioid may be required to prevent OIH [63]. Other NSAIDs administered preemptively also appear to prevent remifentanil-induced hyperalgesia [64].

Another study investigated the effect of intra-operative magnesium sulfate administration in patients undergoing robot-assisted laparoscopic prostatectomy. Magnesium sulfate administration reduced postoperative opioid consumption and OIH in subjects receiving intra-operative remifentanil-based anesthesia [65,66]. Intra-operative adenosine infusion also prevented acute opioid tolerance and remifentanil-induced hyperalgesia [67]. Continuous intra-operative infusion of ketamine, an NMDA receptor antagonist, significant lowered postoperative VAS and morphine use in gynecologic surgery patients [68]. Also, in a randomized, double-blind, placebo-controlled study of 90 patients who underwent total abdominal hysterectomy, cumulative morphine consumption was significantly greater in subjects with fentanyl alone than those with saline alone, ketamine alone, ketamine with fentanyl, or fentanyl with lornoxicam at 3, 6, and 12 hours postoperatively [69].

Finally, in a double-blind, randomized, placebo-controlled study of 40 patients undergoing elective shoulder surgery, clonidine was given intra-operatively in a remifentanil/propofol-based anesthesia. The results showed that clonidine did not reduce postoperative morphine consumption and pain score in these patients [70]. However, dexmedetomidine, another α2 receptor agonist, substantially reduced baseline opioid doses in hospitalized patients with OIH [71].

Quantitative Sensory Testing and OIH

Currently, diagnostic tools for OIH are still being developed. Many clinical studies have used quantitative sensory testing (QST) as a tool to assess OIH [72,73]. In a recent study, QST was used to compare pain threshold, pain tolerance, and the degree of temporal summation of pain in response to thermal stimulation among 3 groups of subjects: Group 1 (no pain and no opioid), Group 2 (chronic pain but no opioid therapy), and Group 3 (both chronic pain and opioid therapy). Group 3 subjects displayed a decreased heat pain threshold and exacerbated temporal summation of pain to thermal stimulation as compared with both group 1 and group 2 subjects. There were no differences in cold or warm sensation among all 3 groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of second pain in group 3 subjects [72]. Another study investigated the sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) using QST in subjects with or without opioid therapy. Pain threshold, intensity and tolerance in response to the cold pressor (1°C) were measured. They found that oral opioid use did not result in abnormal sensitivity to cold pain but altered pain modulation as detected by DNIC [74].

Opioid Regimen and OIH

Opioid regimen features, including type of opioid and dose, may influence the development of OIH. Anecdotal clinical observations have suggested that degree of OIH may vary according to opioid regimen [75]. Although the exact relationship between the dose regimen and the development of OIH remains to be determined, it is conceivable that OIH would be more likely to develop in patients receiving high opioid doses with a prolonged treatment course, although OIH has been demonstrated in patients receiving a short course of highly potent opioid analgesics [76]. Moreover, patients with a pathological pain condition (eg, neuropathic pain) treated with opioid therapy may be more susceptible to developing opioid-induced pain, because both pathological pain and OIH may share a common cellular mechanism [77].

If OIH develops following exposure to one opioid, can switching to a different opioid diminish OIH [78]?If cross-pain sensitivity does not develop between different opioids, switching to a different opioid would be justified, a similar rationale to that for opioid rotation to overcome opioid tolerance. This issue remains to be addressed.

OIH and Pre-emptive Analgesia

There is an ongoing debate about the clinical effectiveness of pre-emptive analgesia in pain management. However, use of opioid analgesic as the sole agent for pre-emptive analgesia may not be desirable for several reasons. First, a large dose of intra-operative opioids could activate a pro-nociceptive mechanism leading to the development of postoperative OIH [79]. This may confound the assessment of postoperative pain and counteract the opioid analgesic effect. Second, pre-emptive analgesia calls for pre-emptive inhibition of neuroplastic changes mediated through multiple cellular mechanisms such as the central glutamatergic system. Paradoxically, opioid administration could activate the central glutamatergic system as discussed above. Third, the neural mechanism of opioid tolerance and OIH may interact with that of pathological pain and pathological pain could be exacerbated following opioid administration [80,81]. This issue needs to be investigated in future studies.

Clinical Implications and Management of OIH

Until recently, a decreased opioid analgesic effect associated with opioid therapy was often recognized as the presence of pharmacologic opioid tolerance (ie, desensitization of the responsiveness of the opioid receptor and its cellular mechanism) and/or a worsening of the clinical pain condition. Therefore, opioid dose escalation appeared to be a logical approach to regain analgesic effectiveness. This practice should be reconsidered in light of the information on OIH. In the clinical setting, apparent opioid tolerance may result from pharmacological tolerance, worsening pain condition due to disease progression, and/or OIH. Below are some factors to consider in forming a differential diagnosis in the clinical setting [82].

First, the quality, location, and distribution pattern of the pain related to OIH would be different from a pre-existing pain condition. Because opioid analgesics are often administered systemically, changes in pain quality would be diffuse as compared with the pre-existing pain condition. Since the mechanism of OIH is similar to that of pathological pain, such as neuropathic pain, changes in pain threshold, tolerability, and distribution patterns seen in OIH would be similar to those seen in neuropathic pain patients. Quantitative sensory testing may be a useful tool to detect such changes.

Second, OIH would possibly exacerbate a pre-existing pain condition. Overall pain intensity (VAS) would be conceivably increased above the level of pre-existing pain in the absence of disease progression. Opioid dose escalation could only transiently and minimally reduce pain intensity in such a setting, with a subsequent increase in pain intensity due to OIH.

Third, when a diagnosis is uncertain, a trial of opioid dose escalation or tapering may be helpful to differentiate between tolerance and OIH. In an undertreated, worsening pain condition due to disease progress and/or pharma-cologic opioid tolerance, improved pain control may well be seen after a trial of opioid dose escalation. On the other hand, opioid dose escalation may exacerbate pain due to OIH, while a supervised opioid tapering may reduce OIH and improve clinical pain management. In this regard, if a patient is on a low opioid dose regimen and complains of unsatisfactory pain relief, a trial of opioid dose escalation may be appropriate; if a patient is already on a high dose of opioid analgesics, further dose escalation is rarely justified and may exacerbate OIH.

It is important to remember that the clinical outcome of opioid therapy is a dynamic balance among the opioid analgesic effect, OIH, and worsening pain due to disease progression. While any opioid dose escalation may transiently increase the analgesic effect, albeit by a small degree in many cases, the real issue is whether the same dose escalation may also exacerbate OIH, which could quickly overtake the transient increase in the opioid analgesic effect. Therefore, clinical judgment is fundamentally important and all clinical conditions related to opioid therapy need to be taken into consideration in the decision making process.

Summary

Interest in understanding OIH has grown over the last decade. Many discussions and reviews have centered around several key issues: (1) opioids not only produce analgesia through their anti-nociceptive effect, but also induce hyperalgesia via a pro-nociceptive effect; (2) opioid tolerance itself may be part of sensitization of a pro-nociceptive process; (3) the onset of OIH may be later than that of opioid tolerance and OIH may be a dose-related process, although OIH has been reported following acute and chronic opioid exposure at both high and low doses; (4) it is unclear whether a certain type of opioid and route of administration may be more likely to lead to clinical presentation of OIH; and (5) although opioid tolerance, OIH, and opioid withdrawal may share some common factors and mechanisms, the mechanism underlying each of these phenomena remains unclear [83].

While OIH has been well documented and investigated over nearly 2 decades, its exact clinical characteristics and underlying mechanisms have yet to be fully determined [84]. In addition, opioid tolerance should be differentiated from OIH, although both have a similar clinical presentation with regard to change in pain intensity [85]. Clinically, OIH should be considered when the adjustment of opioid dose is contemplated if prior opioid dose escalation fails to provide the expected analgesic effect and there is unexplainable pain exacerbation following an initial period of effective opioid analgesia. Although in some cases increasing opioid dose leads to some improvement in pain management, in other cases less opioid may be more effective in pain reduction. This goal may be accomplished by initiating a trial of opioid tapering, opioid rotation, adding adjunctive medications, or combining opioid with a clinically available NMDA receptor antagonist. Continuing opioid therapy with endless dose escalation in the absence of clinical evidence of improved pain management is neither scientifically sound nor clinically justified.

Corresponding author: Lucy L. Chen, MD, MGH Center for Pain Medicine, WACC #340, 15 Parkman St., Boston, MA 02114.

Financial disclosures: None.

From the Massachusetts General Hospital Center for Pain Medicine, Boston, MA.

Abstract

• Objective: To review evidence from clinical and preclinical studies related to the phenomenon of opioid-induced hyperalgesia (OIH) and discuss issues relevant to clinical diagnosis and management.
• Methods: Literature review.
• Results: OIH is defined as a state of nociceptive sensitization caused by exposure to opioids such that a patient receiving opioids to treat pain could become more sensitive to painful stimuli. Interest in understanding OIH has grown over years and multiple mechanisms have been proposed. Both OIH and opioid tolerance can reduce opioid analgesic efficacy, complicating clinical management of chronic pain. When a diagnosis is uncertain, a trial of opioid dose escalation or tapering may be helpful in differentiating between tolerance and OIH. It is unclear whether certain types of opioids or routes of administration are more likely to lead to OIH.
• Conclusion: Clinical outcome of opioid therapy is a dynamic balance among the opioid analgesic effect, OIH, and worsening pain due to disease progression. While OIH has been well documented over nearly 2 decades, its exact clinical characteristics and underlying mechanisms have yet to be fully determined.

Opioids, which produce analgesia through a primarily inhibitory effect on the nociceptive system, have been used for decades for the clinical management of moderate to severe pain. Opioid analgesics act on 3 major classes of opioid receptors, including the µ, k, δ (mu, kappa, and delta) receptors. Activation of opioid receptors not only produces analgesia but also other effects, such as euphoria, respiratory depression, decreased gastrointestinal motility, and cardiovascular effects. Exposure to opioids, however, can also lead to the development of opioid tolerance and opioid-induced hyperalgesia (OIH). Both opioid tolerance and OIH can decrease opioid analgesic efficacy, making chronic pain management a challenge. OIH is a state of nociceptive sensitization caused by exposure to opioids, such that a patient receiving opioids for the treatment of pain could actually become more sensitive to painful stimulation, resulting in a paradoxical adverse response to opioid therapy. In this article, we will review evidence from preclinical and clinical studies and discuss issues relevant to clinical diagnosis and management of OIH.

Evidence of OIH in Animal Studies

In early 1990s, an original preclinical study showed that there was a progressive reduction in baseline nociceptive threshold by using a foot withdraw test in rats receiving repeated intrathecal morphine administration (10-20 mg) over a 7-day period [1]. A number of animal studies later also provided similar data. A reduced baseline nociceptive threshold was observed in animals receiving subcutaneous fentanyl boluses using the Randall-Sellitto test, in which a constantly increasing pressure was applied to a rat’s hind paw. The decreased baseline nociceptive threshold lasted 5 days after cessation of 4 fentanyl bolus injections [2]. In another study, a reduced baseline nociceptive threshold was detected in animals with repeated heroin administration [3]. In other studies, rats exposed to morphine also developed a latent sensitization of visceral pain with a shift of the morphine dose-response curve to the right [4]; exposure to methadone also induced hyperalgesia in rats, which was not prevented by a weak NMDA receptor antagonist (memantine) [5]; and a partial µ-receptor agonist buprenophine produced a dose-related OIH as well [6].

These results indicate that a progressive and lasting reduction of baseline nociceptive threshold, which was referred to as OIH, can result from repeated opioid administration [7–9]. However, different from previous preclinical observations in which a large dose of intrathecal morphine was given, these studies resulted in hyperalgesic response [10,11] in a clinically relevant opioid dose. Of interest is that OIH was observed in animals even when there was continuous opioid infusion via an implanted osmotic pump, suggesting the involvement of active cellular mechanisms in the process [12]. Therefore, prolonged opioid treatment results in not only loss of the opioid analgesic effect (anti-nociceptive effect or desensitization) but also activation of a hyperalgesic effect (a pro-nociceptive effect with reduced nociceptive threshold or increased sensitization). Although both opioid tolerance and OIH are initiated by opioid administration, two opposing cellular mechanisms (ie, desensitization versus sensitization) may be involved in the process. Subsequently, many studies explored the neural and cellular mechanisms underlying the development of OIH and their interaction with the mechanism of opioid tolerance.

Proposed Cellular Mechanisms of OIH

A significant number of recent studies have explored the neurobiological basis of OIH, revealing a divergent range of cellular elements contributory to OIH. These mechanisms include (1) N-methyl-D-aspartate (NMDA) receptor and related intracellular pathways; (2) involvement of G-protein coupled receptors including 5-HT receptors and neurokinin-1 receptors; (3) nitrix oxide and nitric oxide sunthase; (4) TRPV1 receptors; (5) calcium channels; and (6) miscellaneous mechanisms including sex differences [7–9,13–41].

In summary, an increasing number of preclinical studies in the area of OIH indicates that there is enormous interest in understanding the cellular mechanisms of OIH, and the current evidence points to a progressive sensitization process within the central nervous system that involves a constellation of cellular elements such as NMDA receptors, similar to those contributory to the mechanisms of pathological pain.

Evidence of OIH in Human Studies

In animal studies, changes in baseline nociceptive thresholds can be measured in a controlled setting. It is, however, difficult to assess changes in pain threshold in clinical environment following opioid administration [9]. It is often a challenge to distinguish opioid pharmacologic tolerance from OIH because the outcome of opioid therapy is based primarily on subjective pain scores. In the face of these challenges, an increasing number of clinical anecdotal case reports and studies suggest that OIH is likely to be a significant factor in clinical opioid therapy [47–54].

In a study of 1620 patients in which remifentanil was used for general anesthesia, the incidence of postoperative remifentanil-induced hyperalgesia was 16.1%. This study found that age younger than 16 years, male sex, operation duration longer than 2 hours, and remifentanil dose greater than 30 mg/kga were associated with higher rates of OIH [55]. On the other hand, heroin or other opioid addicts not only demonstrated OIH but also had prolonged symptoms of OIH after detoxification from opioids for at least 1 month [56]. In chronic pain patients without opioid dependence, significantly lower pain threshold and tolerance as assessed by pressure pain stimulation were detected [57]. It appears that the sensitivity of detecting OIH in the clinical setting may be influenced by the modality of sensory stimulation [58].

In a prospective preliminary study of 6 patients with chronic low back pain, hyperalgesic response was detected after 1 month of oral morphine therapy using a cold pressor test but not a heat pain test [59]. In another prospective randomized, placebo-controlled, 2-way crossover study in healthy human volunteers, the development of OIH was quantified as changes in the average radius of the area of secondary hyperalgesia generated by electrical pain stimulation. A 23.6% increase in the area of secondary hyperalgesia over baseline was detected following the remifentanil infusion. The same study showed that endogenous opioids did not seem to have an effect on OIH because a single bolus of naloxone did not change the size of secondary hyperalgesia [60].

OIH Prevention Studies

Currently, efforts have also been made to see whether OIH can be prevented with different approaches in human subjects. The following is a brief summary of these studies. In a study of adolescents undergoing scoliosis surgery, treatment with morphine (150 mg/kg) prior to commencing remifentanil infusion did not prevent the development of remifentanil-induced hyperalgesia [61]. In another study, propofol infusion alone with remifentanil both delayed and attenuated remifentanil-induced hyperalgesia [53]. In yet another study, intraoperative 70% N2O administration appeared to reduce postoperative OIH following an intraoperative remifentanil-propofol anesthesia regimen [62].

In a study of 15 healthy male volunteers, preventive administration of parecoxib significantly diminished OIH after withdrawal from remifentanil. In contrast, parecoxib given together with remifentanil did not prevent OIH, suggesting that pre-treatment, not parallel treatment, with opioid may be required to prevent OIH [63]. Other NSAIDs administered preemptively also appear to prevent remifentanil-induced hyperalgesia [64].

Another study investigated the effect of intra-operative magnesium sulfate administration in patients undergoing robot-assisted laparoscopic prostatectomy. Magnesium sulfate administration reduced postoperative opioid consumption and OIH in subjects receiving intra-operative remifentanil-based anesthesia [65,66]. Intra-operative adenosine infusion also prevented acute opioid tolerance and remifentanil-induced hyperalgesia [67]. Continuous intra-operative infusion of ketamine, an NMDA receptor antagonist, significant lowered postoperative VAS and morphine use in gynecologic surgery patients [68]. Also, in a randomized, double-blind, placebo-controlled study of 90 patients who underwent total abdominal hysterectomy, cumulative morphine consumption was significantly greater in subjects with fentanyl alone than those with saline alone, ketamine alone, ketamine with fentanyl, or fentanyl with lornoxicam at 3, 6, and 12 hours postoperatively [69].

Finally, in a double-blind, randomized, placebo-controlled study of 40 patients undergoing elective shoulder surgery, clonidine was given intra-operatively in a remifentanil/propofol-based anesthesia. The results showed that clonidine did not reduce postoperative morphine consumption and pain score in these patients [70]. However, dexmedetomidine, another α2 receptor agonist, substantially reduced baseline opioid doses in hospitalized patients with OIH [71].

Quantitative Sensory Testing and OIH

Currently, diagnostic tools for OIH are still being developed. Many clinical studies have used quantitative sensory testing (QST) as a tool to assess OIH [72,73]. In a recent study, QST was used to compare pain threshold, pain tolerance, and the degree of temporal summation of pain in response to thermal stimulation among 3 groups of subjects: Group 1 (no pain and no opioid), Group 2 (chronic pain but no opioid therapy), and Group 3 (both chronic pain and opioid therapy). Group 3 subjects displayed a decreased heat pain threshold and exacerbated temporal summation of pain to thermal stimulation as compared with both group 1 and group 2 subjects. There were no differences in cold or warm sensation among all 3 groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of second pain in group 3 subjects [72]. Another study investigated the sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) using QST in subjects with or without opioid therapy. Pain threshold, intensity and tolerance in response to the cold pressor (1°C) were measured. They found that oral opioid use did not result in abnormal sensitivity to cold pain but altered pain modulation as detected by DNIC [74].

Opioid Regimen and OIH

Opioid regimen features, including type of opioid and dose, may influence the development of OIH. Anecdotal clinical observations have suggested that degree of OIH may vary according to opioid regimen [75]. Although the exact relationship between the dose regimen and the development of OIH remains to be determined, it is conceivable that OIH would be more likely to develop in patients receiving high opioid doses with a prolonged treatment course, although OIH has been demonstrated in patients receiving a short course of highly potent opioid analgesics [76]. Moreover, patients with a pathological pain condition (eg, neuropathic pain) treated with opioid therapy may be more susceptible to developing opioid-induced pain, because both pathological pain and OIH may share a common cellular mechanism [77].

If OIH develops following exposure to one opioid, can switching to a different opioid diminish OIH [78]?If cross-pain sensitivity does not develop between different opioids, switching to a different opioid would be justified, a similar rationale to that for opioid rotation to overcome opioid tolerance. This issue remains to be addressed.

OIH and Pre-emptive Analgesia

There is an ongoing debate about the clinical effectiveness of pre-emptive analgesia in pain management. However, use of opioid analgesic as the sole agent for pre-emptive analgesia may not be desirable for several reasons. First, a large dose of intra-operative opioids could activate a pro-nociceptive mechanism leading to the development of postoperative OIH [79]. This may confound the assessment of postoperative pain and counteract the opioid analgesic effect. Second, pre-emptive analgesia calls for pre-emptive inhibition of neuroplastic changes mediated through multiple cellular mechanisms such as the central glutamatergic system. Paradoxically, opioid administration could activate the central glutamatergic system as discussed above. Third, the neural mechanism of opioid tolerance and OIH may interact with that of pathological pain and pathological pain could be exacerbated following opioid administration [80,81]. This issue needs to be investigated in future studies.

Clinical Implications and Management of OIH

Until recently, a decreased opioid analgesic effect associated with opioid therapy was often recognized as the presence of pharmacologic opioid tolerance (ie, desensitization of the responsiveness of the opioid receptor and its cellular mechanism) and/or a worsening of the clinical pain condition. Therefore, opioid dose escalation appeared to be a logical approach to regain analgesic effectiveness. This practice should be reconsidered in light of the information on OIH. In the clinical setting, apparent opioid tolerance may result from pharmacological tolerance, worsening pain condition due to disease progression, and/or OIH. Below are some factors to consider in forming a differential diagnosis in the clinical setting [82].

First, the quality, location, and distribution pattern of the pain related to OIH would be different from a pre-existing pain condition. Because opioid analgesics are often administered systemically, changes in pain quality would be diffuse as compared with the pre-existing pain condition. Since the mechanism of OIH is similar to that of pathological pain, such as neuropathic pain, changes in pain threshold, tolerability, and distribution patterns seen in OIH would be similar to those seen in neuropathic pain patients. Quantitative sensory testing may be a useful tool to detect such changes.

Second, OIH would possibly exacerbate a pre-existing pain condition. Overall pain intensity (VAS) would be conceivably increased above the level of pre-existing pain in the absence of disease progression. Opioid dose escalation could only transiently and minimally reduce pain intensity in such a setting, with a subsequent increase in pain intensity due to OIH.

Third, when a diagnosis is uncertain, a trial of opioid dose escalation or tapering may be helpful to differentiate between tolerance and OIH. In an undertreated, worsening pain condition due to disease progress and/or pharma-cologic opioid tolerance, improved pain control may well be seen after a trial of opioid dose escalation. On the other hand, opioid dose escalation may exacerbate pain due to OIH, while a supervised opioid tapering may reduce OIH and improve clinical pain management. In this regard, if a patient is on a low opioid dose regimen and complains of unsatisfactory pain relief, a trial of opioid dose escalation may be appropriate; if a patient is already on a high dose of opioid analgesics, further dose escalation is rarely justified and may exacerbate OIH.

It is important to remember that the clinical outcome of opioid therapy is a dynamic balance among the opioid analgesic effect, OIH, and worsening pain due to disease progression. While any opioid dose escalation may transiently increase the analgesic effect, albeit by a small degree in many cases, the real issue is whether the same dose escalation may also exacerbate OIH, which could quickly overtake the transient increase in the opioid analgesic effect. Therefore, clinical judgment is fundamentally important and all clinical conditions related to opioid therapy need to be taken into consideration in the decision making process.

Summary

Interest in understanding OIH has grown over the last decade. Many discussions and reviews have centered around several key issues: (1) opioids not only produce analgesia through their anti-nociceptive effect, but also induce hyperalgesia via a pro-nociceptive effect; (2) opioid tolerance itself may be part of sensitization of a pro-nociceptive process; (3) the onset of OIH may be later than that of opioid tolerance and OIH may be a dose-related process, although OIH has been reported following acute and chronic opioid exposure at both high and low doses; (4) it is unclear whether a certain type of opioid and route of administration may be more likely to lead to clinical presentation of OIH; and (5) although opioid tolerance, OIH, and opioid withdrawal may share some common factors and mechanisms, the mechanism underlying each of these phenomena remains unclear [83].

While OIH has been well documented and investigated over nearly 2 decades, its exact clinical characteristics and underlying mechanisms have yet to be fully determined [84]. In addition, opioid tolerance should be differentiated from OIH, although both have a similar clinical presentation with regard to change in pain intensity [85]. Clinically, OIH should be considered when the adjustment of opioid dose is contemplated if prior opioid dose escalation fails to provide the expected analgesic effect and there is unexplainable pain exacerbation following an initial period of effective opioid analgesia. Although in some cases increasing opioid dose leads to some improvement in pain management, in other cases less opioid may be more effective in pain reduction. This goal may be accomplished by initiating a trial of opioid tapering, opioid rotation, adding adjunctive medications, or combining opioid with a clinically available NMDA receptor antagonist. Continuing opioid therapy with endless dose escalation in the absence of clinical evidence of improved pain management is neither scientifically sound nor clinically justified.

Corresponding author: Lucy L. Chen, MD, MGH Center for Pain Medicine, WACC #340, 15 Parkman St., Boston, MA 02114.

Financial disclosures: None.

It was the coffee that did it to me. “You can’t have real coffee,” the room service dietary person said, “decaf. You’re on a cardiac diet.” She had already refused my request for orange juice, for waffles, for a short stack of pancakes—“You’re on a diabetic diet.” But, I remonstrated, my sugars are normal and at home I eat a regular diet. “Not on your life,” she replied. You have to get your doctor or your nurse to change the diet order. “You’re on a cardiac-diabetic diet.” But I’ve talked with my cardiologist and he says a couple of cups of coffee a day are OK. “Nope, not from us, it isn’t.”

My last meal was the evening before. Nothing to speak of for breakfast and then no lunch, of course, since my cardiac angiogram had been scheduled for 2:30 pm and then started an hour late. It was now dinner time and I was famished. I especially wanted that cup of coffee. My doctor had gone back to his office and in a hospital staffed with many many nursing people, I didn’t know who my nurse was. Worse yet, I had sent my eyeglasses home with my wife along with my clothes. I couldn’t see the button to summon help (although it wouldn’t have been much help, I also couldn’t see the TV up on the wall). Besides, flat on my back, after strict instructions to lie flat for 12 hours after the angiogram femoral stick, I couldn’t even find the nurse call button.

I tried pulling rank. “I’m a doctor myself, you know.” No luck. The dietary limb of this new hospital stood firm.

Eventually, many hours later (maybe ¾ of an hour), maybe days later, my real nurse came in. She introduced herself, “Susan,” and told me she was to be “my main man” and that “she had the keys to the kingdom.” Specifically, she could change the dietary order. Breakfast appeared at 8 pm. Yum! Real coffee, not decaf.

I was in the hospital to figure out why my angina pectoris had returned.

It arrived about 20 years ago. A diminution in the distance I could run without stopping because of a new sensation, a heavy rock in my chest. No big problem; I could pause for 15 seconds and the pain would subside. So I still ran, just lopping off a few miles each day. And finally I went to see a cardiologist who put me on a treadmill until the ST segments dropped and then he stopped me with an ominous “the test has gone positive.” What does a cardiologist do when his middle-aged physician friend has a positive treadmill test? An angiogram of course. So we soon had pictures of my coronary arteries and yes, there were blockages, but not very severe, maybe I could keep jogging.

It took a few years for the angina to become really disruptive. Another angiogram led to an effort to open up the main obstruction, one-half way down the anterior descending artery, known familiarly as “the artery of sudden death.” OK, let’s do something! And that something was a stent, placed with difficulty and a great deal of chest pain. I think my 2 (now 2 to do this difficult procedure) cardiologists were fearful that they would end with a patent vessel and a dead patient. After the procedure I noted no change in the chest pain trouble but surprise, a belated blood count showed an anemia. So we treated the anemia and the angina got better. I began to wonder if we could have avoided the stenting if we had just checked a hematocrit before the angiogram. But of course, insurance didn’t include that test for that diagnosis.

That was a dozen years ago and the angina remained but at a very stable level. Some of our young physician colleagues use that word “Stable” to mean something that will probably not kill you in the next hour or two. I prefer to use it to mean unchanging. And the angina remained but didn’t change. I had to give up running, a terrible loss for me, but I could walk and do some gym work. I could still read and write and play bridge. Jogging a block or two was enough to bring on the familiar pain; I could give up the jogging.

Then, a year ago the dam broke. My angina increased. Instead of a mile fast walk to provoke it, now a block’s walking did it. And recovery that used to take a few seconds now took a minute or two. We were in Buenos Aires, a city with lots of easy hills, but no longer so easy for me. So I thought it time to go back to the cardiologist. Another angiogram surprised him and me both. The old left coronary artery with its stent was perfectly open, but the right occluded at its orifice and the good Dr. Rainwater couldn’t open it with any of his catheters, wires, or brushes. I needed a real operation, a coronary bypass to that right coronary artery. Not my favorite idea. Joe sent me to a surgeon who he said had the best results in Denver.

Those surgeons love to do what they know how to do. A man with a hammer sees everything as a nail. The surgeon saw me as a bypassable artery.

Big things can be awfully easy to do. I was in and out of the hospital with a nice new bypass in a few days. And though depleted of strength by this strange attack, I happily did not have a pump brain, could still sort a bridge hand, and began my exercise rehabilitation. Within a few weeks I saw hope of regaining strength and no angina. A chance to cut indeed had been a chance to cure.

That was January. Summer spent up in the mountains at 9000 feet, lots of walking, some easy hikes, doing well. And then, all of a sudden, my heart rhythm changed. Frequent premature ventricular beats, often paired to sinus beats (bigemini), sometimes in triplets (trigeminy.) And worse still, I no longer could walk around the block, my usual 3/8 mile with the little dogs had to stop several times with faintness and then with pain. The angina was back, with a vengeance.

So once again to the cardiologist. He and I discussed the odds. 70% probable: something had plugged up, maybe the new graft. If so, he thought I would have to go elsewhere, perhaps to Scripps in San Diego, where people were better at un-plugging vessels with tubes and wires. 5% possibility: plugged vessel that Joe could clear up. That left about a 30% probability: maybe vessels would be OK but it was the fault of the new arrhythmia. And ventricular arrhythmias are notoriously tough to treat. Antiarrhythmia drugs are also all pro-arrhythmic. The treatment may be worse than the disease. I might have become a cardiac cripple.

This was my fourth cardiac angiogram. It seems true that we spend most of our medical expenses in the last year or two of our lives. Maybe that’s where I am. But I agreed—we had to know what was causing the problem even though I didn’t want more dye squirted into my vessels. Well, big surprise and a pleasing one: the coronary vessels were wide open. It was the PVCs that were causing the trouble. So Joe asked Charlie, his electrophysiology pal, to come look at me. Charlie arrived full of joy. He had just the trick. He could stick a few wires into my left ventricle and fry the place that originated the extra beats. How sure was he? Oh, maybe 90% sure—if the wires didn’t perforate the heart wall and if he fried the right spot, maybe I’d be better. Oh? I wondered if there weren’t any drugs, any pills to try first. Yes, he grudgingly admitted, but seldom successfully. Well, let’s try.

The nurse brought me a single pill, approved for treating atrial arrhythmias, not the ventricular extra beats that were attacking me. But nonetheless, 2 hours later an ECG showed 3 PVCs per minute. There had been 30 before. The new drug works! Hooray!

And the coffee had been great.

But I want to tell you about the 2 days in the hospital, when my nurse Susan told me what she had figured out. Her father was a physician, in fact, a fellow I knew well. He had cancer and was suffering chemotherapy. She said that the hardest part for him was giving up control. “You doctors are used to being in charge,” she said. “Now you’re gone over to the other side.” That was it. The total loss of control—of my chest pain, of the cardiac arrhythmia, even of the head of the bed and a late breakfast. That coffee was the worst. I didn’t want decaf.

Once understood by Susan and then even by me, the loss of control seemed less painful. And now the PVCs are almost gone, the chest pain has vanished, and I’m back to walking my 2 little dogs a half a mile 3 times a day.

Corresponding author: Frederic W. Platt, MD, 396 Steele St., Denver, CO 80206, [email protected].

It was the coffee that did it to me. “You can’t have real coffee,” the room service dietary person said, “decaf. You’re on a cardiac diet.” She had already refused my request for orange juice, for waffles, for a short stack of pancakes—“You’re on a diabetic diet.” But, I remonstrated, my sugars are normal and at home I eat a regular diet. “Not on your life,” she replied. You have to get your doctor or your nurse to change the diet order. “You’re on a cardiac-diabetic diet.” But I’ve talked with my cardiologist and he says a couple of cups of coffee a day are OK. “Nope, not from us, it isn’t.”

My last meal was the evening before. Nothing to speak of for breakfast and then no lunch, of course, since my cardiac angiogram had been scheduled for 2:30 pm and then started an hour late. It was now dinner time and I was famished. I especially wanted that cup of coffee. My doctor had gone back to his office and in a hospital staffed with many many nursing people, I didn’t know who my nurse was. Worse yet, I had sent my eyeglasses home with my wife along with my clothes. I couldn’t see the button to summon help (although it wouldn’t have been much help, I also couldn’t see the TV up on the wall). Besides, flat on my back, after strict instructions to lie flat for 12 hours after the angiogram femoral stick, I couldn’t even find the nurse call button.

I tried pulling rank. “I’m a doctor myself, you know.” No luck. The dietary limb of this new hospital stood firm.

Eventually, many hours later (maybe ¾ of an hour), maybe days later, my real nurse came in. She introduced herself, “Susan,” and told me she was to be “my main man” and that “she had the keys to the kingdom.” Specifically, she could change the dietary order. Breakfast appeared at 8 pm. Yum! Real coffee, not decaf.

I was in the hospital to figure out why my angina pectoris had returned.

It arrived about 20 years ago. A diminution in the distance I could run without stopping because of a new sensation, a heavy rock in my chest. No big problem; I could pause for 15 seconds and the pain would subside. So I still ran, just lopping off a few miles each day. And finally I went to see a cardiologist who put me on a treadmill until the ST segments dropped and then he stopped me with an ominous “the test has gone positive.” What does a cardiologist do when his middle-aged physician friend has a positive treadmill test? An angiogram of course. So we soon had pictures of my coronary arteries and yes, there were blockages, but not very severe, maybe I could keep jogging.

It took a few years for the angina to become really disruptive. Another angiogram led to an effort to open up the main obstruction, one-half way down the anterior descending artery, known familiarly as “the artery of sudden death.” OK, let’s do something! And that something was a stent, placed with difficulty and a great deal of chest pain. I think my 2 (now 2 to do this difficult procedure) cardiologists were fearful that they would end with a patent vessel and a dead patient. After the procedure I noted no change in the chest pain trouble but surprise, a belated blood count showed an anemia. So we treated the anemia and the angina got better. I began to wonder if we could have avoided the stenting if we had just checked a hematocrit before the angiogram. But of course, insurance didn’t include that test for that diagnosis.

That was a dozen years ago and the angina remained but at a very stable level. Some of our young physician colleagues use that word “Stable” to mean something that will probably not kill you in the next hour or two. I prefer to use it to mean unchanging. And the angina remained but didn’t change. I had to give up running, a terrible loss for me, but I could walk and do some gym work. I could still read and write and play bridge. Jogging a block or two was enough to bring on the familiar pain; I could give up the jogging.

Then, a year ago the dam broke. My angina increased. Instead of a mile fast walk to provoke it, now a block’s walking did it. And recovery that used to take a few seconds now took a minute or two. We were in Buenos Aires, a city with lots of easy hills, but no longer so easy for me. So I thought it time to go back to the cardiologist. Another angiogram surprised him and me both. The old left coronary artery with its stent was perfectly open, but the right occluded at its orifice and the good Dr. Rainwater couldn’t open it with any of his catheters, wires, or brushes. I needed a real operation, a coronary bypass to that right coronary artery. Not my favorite idea. Joe sent me to a surgeon who he said had the best results in Denver.

Those surgeons love to do what they know how to do. A man with a hammer sees everything as a nail. The surgeon saw me as a bypassable artery.

Big things can be awfully easy to do. I was in and out of the hospital with a nice new bypass in a few days. And though depleted of strength by this strange attack, I happily did not have a pump brain, could still sort a bridge hand, and began my exercise rehabilitation. Within a few weeks I saw hope of regaining strength and no angina. A chance to cut indeed had been a chance to cure.

That was January. Summer spent up in the mountains at 9000 feet, lots of walking, some easy hikes, doing well. And then, all of a sudden, my heart rhythm changed. Frequent premature ventricular beats, often paired to sinus beats (bigemini), sometimes in triplets (trigeminy.) And worse still, I no longer could walk around the block, my usual 3/8 mile with the little dogs had to stop several times with faintness and then with pain. The angina was back, with a vengeance.

So once again to the cardiologist. He and I discussed the odds. 70% probable: something had plugged up, maybe the new graft. If so, he thought I would have to go elsewhere, perhaps to Scripps in San Diego, where people were better at un-plugging vessels with tubes and wires. 5% possibility: plugged vessel that Joe could clear up. That left about a 30% probability: maybe vessels would be OK but it was the fault of the new arrhythmia. And ventricular arrhythmias are notoriously tough to treat. Antiarrhythmia drugs are also all pro-arrhythmic. The treatment may be worse than the disease. I might have become a cardiac cripple.

This was my fourth cardiac angiogram. It seems true that we spend most of our medical expenses in the last year or two of our lives. Maybe that’s where I am. But I agreed—we had to know what was causing the problem even though I didn’t want more dye squirted into my vessels. Well, big surprise and a pleasing one: the coronary vessels were wide open. It was the PVCs that were causing the trouble. So Joe asked Charlie, his electrophysiology pal, to come look at me. Charlie arrived full of joy. He had just the trick. He could stick a few wires into my left ventricle and fry the place that originated the extra beats. How sure was he? Oh, maybe 90% sure—if the wires didn’t perforate the heart wall and if he fried the right spot, maybe I’d be better. Oh? I wondered if there weren’t any drugs, any pills to try first. Yes, he grudgingly admitted, but seldom successfully. Well, let’s try.

The nurse brought me a single pill, approved for treating atrial arrhythmias, not the ventricular extra beats that were attacking me. But nonetheless, 2 hours later an ECG showed 3 PVCs per minute. There had been 30 before. The new drug works! Hooray!

And the coffee had been great.

But I want to tell you about the 2 days in the hospital, when my nurse Susan told me what she had figured out. Her father was a physician, in fact, a fellow I knew well. He had cancer and was suffering chemotherapy. She said that the hardest part for him was giving up control. “You doctors are used to being in charge,” she said. “Now you’re gone over to the other side.” That was it. The total loss of control—of my chest pain, of the cardiac arrhythmia, even of the head of the bed and a late breakfast. That coffee was the worst. I didn’t want decaf.

Once understood by Susan and then even by me, the loss of control seemed less painful. And now the PVCs are almost gone, the chest pain has vanished, and I’m back to walking my 2 little dogs a half a mile 3 times a day.

Corresponding author: Frederic W. Platt, MD, 396 Steele St., Denver, CO 80206, [email protected].

It was the coffee that did it to me. “You can’t have real coffee,” the room service dietary person said, “decaf. You’re on a cardiac diet.” She had already refused my request for orange juice, for waffles, for a short stack of pancakes—“You’re on a diabetic diet.” But, I remonstrated, my sugars are normal and at home I eat a regular diet. “Not on your life,” she replied. You have to get your doctor or your nurse to change the diet order. “You’re on a cardiac-diabetic diet.” But I’ve talked with my cardiologist and he says a couple of cups of coffee a day are OK. “Nope, not from us, it isn’t.”

My last meal was the evening before. Nothing to speak of for breakfast and then no lunch, of course, since my cardiac angiogram had been scheduled for 2:30 pm and then started an hour late. It was now dinner time and I was famished. I especially wanted that cup of coffee. My doctor had gone back to his office and in a hospital staffed with many many nursing people, I didn’t know who my nurse was. Worse yet, I had sent my eyeglasses home with my wife along with my clothes. I couldn’t see the button to summon help (although it wouldn’t have been much help, I also couldn’t see the TV up on the wall). Besides, flat on my back, after strict instructions to lie flat for 12 hours after the angiogram femoral stick, I couldn’t even find the nurse call button.

I tried pulling rank. “I’m a doctor myself, you know.” No luck. The dietary limb of this new hospital stood firm.

Eventually, many hours later (maybe ¾ of an hour), maybe days later, my real nurse came in. She introduced herself, “Susan,” and told me she was to be “my main man” and that “she had the keys to the kingdom.” Specifically, she could change the dietary order. Breakfast appeared at 8 pm. Yum! Real coffee, not decaf.

I was in the hospital to figure out why my angina pectoris had returned.

It arrived about 20 years ago. A diminution in the distance I could run without stopping because of a new sensation, a heavy rock in my chest. No big problem; I could pause for 15 seconds and the pain would subside. So I still ran, just lopping off a few miles each day. And finally I went to see a cardiologist who put me on a treadmill until the ST segments dropped and then he stopped me with an ominous “the test has gone positive.” What does a cardiologist do when his middle-aged physician friend has a positive treadmill test? An angiogram of course. So we soon had pictures of my coronary arteries and yes, there were blockages, but not very severe, maybe I could keep jogging.

It took a few years for the angina to become really disruptive. Another angiogram led to an effort to open up the main obstruction, one-half way down the anterior descending artery, known familiarly as “the artery of sudden death.” OK, let’s do something! And that something was a stent, placed with difficulty and a great deal of chest pain. I think my 2 (now 2 to do this difficult procedure) cardiologists were fearful that they would end with a patent vessel and a dead patient. After the procedure I noted no change in the chest pain trouble but surprise, a belated blood count showed an anemia. So we treated the anemia and the angina got better. I began to wonder if we could have avoided the stenting if we had just checked a hematocrit before the angiogram. But of course, insurance didn’t include that test for that diagnosis.

That was a dozen years ago and the angina remained but at a very stable level. Some of our young physician colleagues use that word “Stable” to mean something that will probably not kill you in the next hour or two. I prefer to use it to mean unchanging. And the angina remained but didn’t change. I had to give up running, a terrible loss for me, but I could walk and do some gym work. I could still read and write and play bridge. Jogging a block or two was enough to bring on the familiar pain; I could give up the jogging.

Then, a year ago the dam broke. My angina increased. Instead of a mile fast walk to provoke it, now a block’s walking did it. And recovery that used to take a few seconds now took a minute or two. We were in Buenos Aires, a city with lots of easy hills, but no longer so easy for me. So I thought it time to go back to the cardiologist. Another angiogram surprised him and me both. The old left coronary artery with its stent was perfectly open, but the right occluded at its orifice and the good Dr. Rainwater couldn’t open it with any of his catheters, wires, or brushes. I needed a real operation, a coronary bypass to that right coronary artery. Not my favorite idea. Joe sent me to a surgeon who he said had the best results in Denver.

Those surgeons love to do what they know how to do. A man with a hammer sees everything as a nail. The surgeon saw me as a bypassable artery.

Big things can be awfully easy to do. I was in and out of the hospital with a nice new bypass in a few days. And though depleted of strength by this strange attack, I happily did not have a pump brain, could still sort a bridge hand, and began my exercise rehabilitation. Within a few weeks I saw hope of regaining strength and no angina. A chance to cut indeed had been a chance to cure.

That was January. Summer spent up in the mountains at 9000 feet, lots of walking, some easy hikes, doing well. And then, all of a sudden, my heart rhythm changed. Frequent premature ventricular beats, often paired to sinus beats (bigemini), sometimes in triplets (trigeminy.) And worse still, I no longer could walk around the block, my usual 3/8 mile with the little dogs had to stop several times with faintness and then with pain. The angina was back, with a vengeance.

So once again to the cardiologist. He and I discussed the odds. 70% probable: something had plugged up, maybe the new graft. If so, he thought I would have to go elsewhere, perhaps to Scripps in San Diego, where people were better at un-plugging vessels with tubes and wires. 5% possibility: plugged vessel that Joe could clear up. That left about a 30% probability: maybe vessels would be OK but it was the fault of the new arrhythmia. And ventricular arrhythmias are notoriously tough to treat. Antiarrhythmia drugs are also all pro-arrhythmic. The treatment may be worse than the disease. I might have become a cardiac cripple.

This was my fourth cardiac angiogram. It seems true that we spend most of our medical expenses in the last year or two of our lives. Maybe that’s where I am. But I agreed—we had to know what was causing the problem even though I didn’t want more dye squirted into my vessels. Well, big surprise and a pleasing one: the coronary vessels were wide open. It was the PVCs that were causing the trouble. So Joe asked Charlie, his electrophysiology pal, to come look at me. Charlie arrived full of joy. He had just the trick. He could stick a few wires into my left ventricle and fry the place that originated the extra beats. How sure was he? Oh, maybe 90% sure—if the wires didn’t perforate the heart wall and if he fried the right spot, maybe I’d be better. Oh? I wondered if there weren’t any drugs, any pills to try first. Yes, he grudgingly admitted, but seldom successfully. Well, let’s try.

The nurse brought me a single pill, approved for treating atrial arrhythmias, not the ventricular extra beats that were attacking me. But nonetheless, 2 hours later an ECG showed 3 PVCs per minute. There had been 30 before. The new drug works! Hooray!

And the coffee had been great.

But I want to tell you about the 2 days in the hospital, when my nurse Susan told me what she had figured out. Her father was a physician, in fact, a fellow I knew well. He had cancer and was suffering chemotherapy. She said that the hardest part for him was giving up control. “You doctors are used to being in charge,” she said. “Now you’re gone over to the other side.” That was it. The total loss of control—of my chest pain, of the cardiac arrhythmia, even of the head of the bed and a late breakfast. That coffee was the worst. I didn’t want decaf.

Once understood by Susan and then even by me, the loss of control seemed less painful. And now the PVCs are almost gone, the chest pain has vanished, and I’m back to walking my 2 little dogs a half a mile 3 times a day.

Corresponding author: Frederic W. Platt, MD, 396 Steele St., Denver, CO 80206, [email protected].

Study Overview

Objective. To compare the effectiveness and safety of “sequential” and “concomitant” regimens for H. pylori eradication in a setting with increased rates of clarithromycin resistance.

Design. Prospective, multi-center, randomized controlled trial using an intention-to treat and a per-protocol analysis (patients who adhered to study protocol and had a medication compliance of ≥ 90%).

Settings and participants. Patients from 11 Spanish hospitals with confirmed H. pylori infection were invited to participate from December 2010 to May 2012. Participants were at least 18 years old with either non-investigated/functional dyspepsia or gastric/duodenal ulcer. Exclusion criteria included patients with prior H. pylori eradication treatment, the use of bismuth salts or antibiotics for 4 weeks prior to study inclusion, advanced chronic disease that would preclude study completion or follow-up visits, pregnant or breastfeeding patients, as well as patients with prior gastric surgery or alcohol or drug abuse. Participants were allocated using computerized randomization. Study physicians obtained informed consent in the outpatient clinic setting as well as disclosed study arm assignment and dispersed study drugs to participants. The study was unblinded since the number of study drugs and dosing regimens differed between treatment arms.

Intervention. The sequential treatment group received 5 days of dual therapy with omeprazole 20 mg and amoxicillin 1 g every 12 hours, followed by 5 days of triple therapy with omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. The concomitant treatment group received 10 days of quadruple therapy with omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. All drugs were of generic branding.

Main outcome measures. The primary outcome measure was eradication of H. pylori infection confirmed by C-urea breath test or histology a minimum of 4 weeks after ending treatment; secondary outcome was treatment regimen compliance of at least 90% with each study drug.

Main results. 338 patients were randomized, 170 to sequential treatment and 168 to concomitant treatment. There was no significant difference between the 2 arms in relation to age or gender. The average age of participants was similar (47.5 vs 47.3 years in the sequential and concomitant groups, respectively). Women comprised 58.8% of the sequential treatment population and 62.5% of the concomitant population. 95% of both study arms finished treatment.

There was no difference in the primary outcome of eradication of H. pylori infection between the 2 treatment groups in the intention-to-treat analysis as well as in the per-protocol analysis (81.2% vs 86.9%, P = 0.15, and 85.6% vs 91.2%, P = 0.14, in the sequential and concomitant treatment groups, respectively). No statistically significant differences were found between treatment groups based on type of underlying disease. Treatment regimen compliance was also not statistically different between treatment regimens (82.4% sequential vs 82.7% concomitant).

The 2 treatment regimens did not differ significantly in terms of rate and severity of adverse events (P = 0.09). Overall, adverse reactions were reported in 58.6% of the study patients (54.1% in the sequential treatment arm and 63.1% in the concomitant treatment arm). The most common adverse reactions were taste distortions (35.9%), diarrhea (20.1%), and nausea (10.8%). Overall these adverse reactions were characterized as mild (59.2%), moderate (36.2%), and severe (5%).

Conclusion. There was no significant difference between treatment outcomes. Both treatments arms were found to have acceptable compliance and safety profiles.

Commentary

Gastric cancer is the fifth most common malignancy in the world and the third leading cause of cancer death, with estimates of almost 1 million new cases for the year 2012 leading to over 720,000 deaths [1]. On a national level, gastric cancer is less common, with estimates of 21,600 new cases for the year 2013 (1.3% of new cancer cases), leading to an estimated 10,990 deaths (1.9% of all cancer deaths) [2]. Infection with H. pylori is the major risk factor for noncardia gastric cancer (cancer in all areas of the stomach, except for the top portion near where it joins the esophagus) and has been implicated in the development of peptic ulcer disease, chronic gastritis, gastric B-cell mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma [3].

The American College of Gastroenterology [4] and the European Consensus guidelines [5] provide evidence-based recommendations for H. pylori treatment. Standard triple therapy with a proton-pump inhibitor (PPI), clarithromycin, and amoxicillin remains the most widely prescribed regimen, although increasing rates of clarithromycin resistance as well as decreasing rates of H. pylori eradication have prompted investigations of alternative medication and dosing regimens [6].

The present study assesses the efficacy of concomitant therapy for 10 days compared with sequential therapy (omeprazole plus amoxicillin for 5 days, followed by omeprazole, clarithromycin and metronidazole for 5 days). The authors found similar compliance and safety profile rates between the 2 groups, and no significant differences in terms of H. pylori eradication rates. In multivariate analysis, eradication was not associated with patient age, sex, treatment hospital, type of treatment, smoking habit, or presence of ulcer, but was associated with compliance. A strength of this study is the prospective, randomized design, with 11 Spanish hospitals participating. Another strength is the high retention rate, with 95% of subjects completing the trial. A limitation of the trial, as noted by the authors, was not assessing antibiotic resistance in the study patients. This is a relevant omission due to clarithromycin resistance rates in Spain of approximately 14%, which could influence the efficacy of H. pylori eradication when using clarithromycin. Lastly, this study assessed eradication of H. pylori at an interval of at least 4 weeks post-treatment, whereas other investigations have used longer time intervals. Future efforts could assess for H. pylori at an interval of at least 8 weeks post-treatment in order to further validate efficacy of eradication treatment.

Applications for Clinical Practice

Non-bismuth, quadruple concomitant therapy appears to be an effective, safe, well-tolerated and less complex alternative than sequential therapy for H. pylori eradication.  Therefore, this regimen appears well suited for use in settings where efficacy of triple therapy is unacceptably low, either due to increasing rates of clarithromycin resistance and/or decreasing rates of H. pylori eradication.

—Kristen R. Weaver, ACNP-BC, ANP-BC and Allison Squires, PhD, RN

Study Overview

Objective. To compare the effectiveness and safety of “sequential” and “concomitant” regimens for H. pylori eradication in a setting with increased rates of clarithromycin resistance.

Design. Prospective, multi-center, randomized controlled trial using an intention-to treat and a per-protocol analysis (patients who adhered to study protocol and had a medication compliance of ≥ 90%).

Settings and participants. Patients from 11 Spanish hospitals with confirmed H. pylori infection were invited to participate from December 2010 to May 2012. Participants were at least 18 years old with either non-investigated/functional dyspepsia or gastric/duodenal ulcer. Exclusion criteria included patients with prior H. pylori eradication treatment, the use of bismuth salts or antibiotics for 4 weeks prior to study inclusion, advanced chronic disease that would preclude study completion or follow-up visits, pregnant or breastfeeding patients, as well as patients with prior gastric surgery or alcohol or drug abuse. Participants were allocated using computerized randomization. Study physicians obtained informed consent in the outpatient clinic setting as well as disclosed study arm assignment and dispersed study drugs to participants. The study was unblinded since the number of study drugs and dosing regimens differed between treatment arms.

Intervention. The sequential treatment group received 5 days of dual therapy with omeprazole 20 mg and amoxicillin 1 g every 12 hours, followed by 5 days of triple therapy with omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. The concomitant treatment group received 10 days of quadruple therapy with omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. All drugs were of generic branding.

Main outcome measures. The primary outcome measure was eradication of H. pylori infection confirmed by C-urea breath test or histology a minimum of 4 weeks after ending treatment; secondary outcome was treatment regimen compliance of at least 90% with each study drug.

Main results. 338 patients were randomized, 170 to sequential treatment and 168 to concomitant treatment. There was no significant difference between the 2 arms in relation to age or gender. The average age of participants was similar (47.5 vs 47.3 years in the sequential and concomitant groups, respectively). Women comprised 58.8% of the sequential treatment population and 62.5% of the concomitant population. 95% of both study arms finished treatment.

There was no difference in the primary outcome of eradication of H. pylori infection between the 2 treatment groups in the intention-to-treat analysis as well as in the per-protocol analysis (81.2% vs 86.9%, P = 0.15, and 85.6% vs 91.2%, P = 0.14, in the sequential and concomitant treatment groups, respectively). No statistically significant differences were found between treatment groups based on type of underlying disease. Treatment regimen compliance was also not statistically different between treatment regimens (82.4% sequential vs 82.7% concomitant).

The 2 treatment regimens did not differ significantly in terms of rate and severity of adverse events (P = 0.09). Overall, adverse reactions were reported in 58.6% of the study patients (54.1% in the sequential treatment arm and 63.1% in the concomitant treatment arm). The most common adverse reactions were taste distortions (35.9%), diarrhea (20.1%), and nausea (10.8%). Overall these adverse reactions were characterized as mild (59.2%), moderate (36.2%), and severe (5%).

Conclusion. There was no significant difference between treatment outcomes. Both treatments arms were found to have acceptable compliance and safety profiles.

Commentary

Gastric cancer is the fifth most common malignancy in the world and the third leading cause of cancer death, with estimates of almost 1 million new cases for the year 2012 leading to over 720,000 deaths [1]. On a national level, gastric cancer is less common, with estimates of 21,600 new cases for the year 2013 (1.3% of new cancer cases), leading to an estimated 10,990 deaths (1.9% of all cancer deaths) [2]. Infection with H. pylori is the major risk factor for noncardia gastric cancer (cancer in all areas of the stomach, except for the top portion near where it joins the esophagus) and has been implicated in the development of peptic ulcer disease, chronic gastritis, gastric B-cell mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma [3].

The American College of Gastroenterology [4] and the European Consensus guidelines [5] provide evidence-based recommendations for H. pylori treatment. Standard triple therapy with a proton-pump inhibitor (PPI), clarithromycin, and amoxicillin remains the most widely prescribed regimen, although increasing rates of clarithromycin resistance as well as decreasing rates of H. pylori eradication have prompted investigations of alternative medication and dosing regimens [6].

The present study assesses the efficacy of concomitant therapy for 10 days compared with sequential therapy (omeprazole plus amoxicillin for 5 days, followed by omeprazole, clarithromycin and metronidazole for 5 days). The authors found similar compliance and safety profile rates between the 2 groups, and no significant differences in terms of H. pylori eradication rates. In multivariate analysis, eradication was not associated with patient age, sex, treatment hospital, type of treatment, smoking habit, or presence of ulcer, but was associated with compliance. A strength of this study is the prospective, randomized design, with 11 Spanish hospitals participating. Another strength is the high retention rate, with 95% of subjects completing the trial. A limitation of the trial, as noted by the authors, was not assessing antibiotic resistance in the study patients. This is a relevant omission due to clarithromycin resistance rates in Spain of approximately 14%, which could influence the efficacy of H. pylori eradication when using clarithromycin. Lastly, this study assessed eradication of H. pylori at an interval of at least 4 weeks post-treatment, whereas other investigations have used longer time intervals. Future efforts could assess for H. pylori at an interval of at least 8 weeks post-treatment in order to further validate efficacy of eradication treatment.

Applications for Clinical Practice

Non-bismuth, quadruple concomitant therapy appears to be an effective, safe, well-tolerated and less complex alternative than sequential therapy for H. pylori eradication.  Therefore, this regimen appears well suited for use in settings where efficacy of triple therapy is unacceptably low, either due to increasing rates of clarithromycin resistance and/or decreasing rates of H. pylori eradication.

—Kristen R. Weaver, ACNP-BC, ANP-BC and Allison Squires, PhD, RN

Study Overview

Objective. To compare the effectiveness and safety of “sequential” and “concomitant” regimens for H. pylori eradication in a setting with increased rates of clarithromycin resistance.

Design. Prospective, multi-center, randomized controlled trial using an intention-to treat and a per-protocol analysis (patients who adhered to study protocol and had a medication compliance of ≥ 90%).

Settings and participants. Patients from 11 Spanish hospitals with confirmed H. pylori infection were invited to participate from December 2010 to May 2012. Participants were at least 18 years old with either non-investigated/functional dyspepsia or gastric/duodenal ulcer. Exclusion criteria included patients with prior H. pylori eradication treatment, the use of bismuth salts or antibiotics for 4 weeks prior to study inclusion, advanced chronic disease that would preclude study completion or follow-up visits, pregnant or breastfeeding patients, as well as patients with prior gastric surgery or alcohol or drug abuse. Participants were allocated using computerized randomization. Study physicians obtained informed consent in the outpatient clinic setting as well as disclosed study arm assignment and dispersed study drugs to participants. The study was unblinded since the number of study drugs and dosing regimens differed between treatment arms.

Intervention. The sequential treatment group received 5 days of dual therapy with omeprazole 20 mg and amoxicillin 1 g every 12 hours, followed by 5 days of triple therapy with omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. The concomitant treatment group received 10 days of quadruple therapy with omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours. All drugs were of generic branding.

Main outcome measures. The primary outcome measure was eradication of H. pylori infection confirmed by C-urea breath test or histology a minimum of 4 weeks after ending treatment; secondary outcome was treatment regimen compliance of at least 90% with each study drug.

Main results. 338 patients were randomized, 170 to sequential treatment and 168 to concomitant treatment. There was no significant difference between the 2 arms in relation to age or gender. The average age of participants was similar (47.5 vs 47.3 years in the sequential and concomitant groups, respectively). Women comprised 58.8% of the sequential treatment population and 62.5% of the concomitant population. 95% of both study arms finished treatment.

There was no difference in the primary outcome of eradication of H. pylori infection between the 2 treatment groups in the intention-to-treat analysis as well as in the per-protocol analysis (81.2% vs 86.9%, P = 0.15, and 85.6% vs 91.2%, P = 0.14, in the sequential and concomitant treatment groups, respectively). No statistically significant differences were found between treatment groups based on type of underlying disease. Treatment regimen compliance was also not statistically different between treatment regimens (82.4% sequential vs 82.7% concomitant).

The 2 treatment regimens did not differ significantly in terms of rate and severity of adverse events (P = 0.09). Overall, adverse reactions were reported in 58.6% of the study patients (54.1% in the sequential treatment arm and 63.1% in the concomitant treatment arm). The most common adverse reactions were taste distortions (35.9%), diarrhea (20.1%), and nausea (10.8%). Overall these adverse reactions were characterized as mild (59.2%), moderate (36.2%), and severe (5%).

Conclusion. There was no significant difference between treatment outcomes. Both treatments arms were found to have acceptable compliance and safety profiles.

Commentary

Gastric cancer is the fifth most common malignancy in the world and the third leading cause of cancer death, with estimates of almost 1 million new cases for the year 2012 leading to over 720,000 deaths [1]. On a national level, gastric cancer is less common, with estimates of 21,600 new cases for the year 2013 (1.3% of new cancer cases), leading to an estimated 10,990 deaths (1.9% of all cancer deaths) [2]. Infection with H. pylori is the major risk factor for noncardia gastric cancer (cancer in all areas of the stomach, except for the top portion near where it joins the esophagus) and has been implicated in the development of peptic ulcer disease, chronic gastritis, gastric B-cell mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma [3].

The American College of Gastroenterology [4] and the European Consensus guidelines [5] provide evidence-based recommendations for H. pylori treatment. Standard triple therapy with a proton-pump inhibitor (PPI), clarithromycin, and amoxicillin remains the most widely prescribed regimen, although increasing rates of clarithromycin resistance as well as decreasing rates of H. pylori eradication have prompted investigations of alternative medication and dosing regimens [6].

The present study assesses the efficacy of concomitant therapy for 10 days compared with sequential therapy (omeprazole plus amoxicillin for 5 days, followed by omeprazole, clarithromycin and metronidazole for 5 days). The authors found similar compliance and safety profile rates between the 2 groups, and no significant differences in terms of H. pylori eradication rates. In multivariate analysis, eradication was not associated with patient age, sex, treatment hospital, type of treatment, smoking habit, or presence of ulcer, but was associated with compliance. A strength of this study is the prospective, randomized design, with 11 Spanish hospitals participating. Another strength is the high retention rate, with 95% of subjects completing the trial. A limitation of the trial, as noted by the authors, was not assessing antibiotic resistance in the study patients. This is a relevant omission due to clarithromycin resistance rates in Spain of approximately 14%, which could influence the efficacy of H. pylori eradication when using clarithromycin. Lastly, this study assessed eradication of H. pylori at an interval of at least 4 weeks post-treatment, whereas other investigations have used longer time intervals. Future efforts could assess for H. pylori at an interval of at least 8 weeks post-treatment in order to further validate efficacy of eradication treatment.

Applications for Clinical Practice

Non-bismuth, quadruple concomitant therapy appears to be an effective, safe, well-tolerated and less complex alternative than sequential therapy for H. pylori eradication.  Therefore, this regimen appears well suited for use in settings where efficacy of triple therapy is unacceptably low, either due to increasing rates of clarithromycin resistance and/or decreasing rates of H. pylori eradication.

—Kristen R. Weaver, ACNP-BC, ANP-BC and Allison Squires, PhD, RN

Study Overview

Objective. To systematically review randomized controlled trials (RCTs) examining the effects of exercise interventions on cancer-related fatigue (CRF) in patients during and after treatment to determine differential effects.

Design. Meta-analysis.

Data. 70 RCTs with a combined sample of 4881 oncology patients during active treatment (eg, chemotherapy, radiation therapy, hormone therapy) or after completion of treatment published before August 2011 that analyzed the effect on CRF of an exercise program compared with a non-exercise control. Excluded from analysis were RCTs that compared exercise with other types of interventions (ie, education, pharmacotherapy, different methods of exercise). 43 studies examined exercise during treatment while 27 studied the effects after treatment.

Measurement. Effect size was calculated to determine the magnitude of the effect of exercise on improving CRF.

Main results. The effect size (Δ = 0.34, P < 0.001) for the total sample of 70 RCTs indicated that exercise has a moderate effect on CRF regardless of treatment status. When effect sizes were calculated for the 43 RCTs that examined patients during treatment, exercise was found to significantly decrease CRF (Δ = 0.32, P < 0.001). Based on calculated effect size for the 27 RCTs that examined exercise after treatment completion, exercise continues to significantly decrease CRF (Δ = 0.38, P < 0.001). The effect of exercise on CRF was consistent not only during or after treatment, but also across cancer diagnosis, patient age, and sex.

Exercise reduces CRF both during and after treatment. In patients who exercise, CRF severity decreases by 4.9% compared to a 29.1% increase in CRF in patients who do not exercise. After treatment, exercise decreases CRF by 20.5% compared to a decrease of 1.3% in patients who do not exercise.

Both during and after treatment, patients with higher exercise adherence experienced the most improvement (P < 0.001). Patients in active treatment with less severe baseline CRF demonstrated greater adherence to the exercise program and saw greater improvements in CRF. Patients who were further from active treatment saw greater CRF severity reduction than patients closer to active treatment. After treatment, the longer the exercise program, the more effective it was in decreasing CRF. No specific type of exercise program (eg, home-based, supervised, vigorous, moderate) was shown to be more effective than another.

Conclusion. Exercise decreases CRF in patients during and after treatment. The type of exercise does not change the positive effect of exercise, so it is important to encourage patients to be active.

Commentary

Cancer-related fatigue (CRF) is the most disturbing symptom associated with cancer diagnosis and its treatment [1]. Defined as a persistent, subjective sense of tiredness that is not proportional to activity and not relieved by rest, CRF is reported in over 80% of oncology patients during active treatment [1]. This symptom is not limited to the active treatment phase, with over 30% of cancer survivors reporting CRF lasting at least 5 years [2]. CRF is associated with decreased quality of life (QOL), decreased functional status, and decreased participation in social activities [1]. The pathogenesis of CRF is not fully understood [3,4]. Disruptions in biochemical pathways [5], genome expression [6] chemotherapy or radiation treatments [7,8], cancer pathogenesis [4], or a combination of factors [9] are hypothesized as contributing to the development and severity of CRF. The complexity of CRF pathogenesis makes clinical management difficult.

The current meta-analysis suggests that exercise is an effective nonpharmacologic intervention to ameliorate the impact of this devastating symptom and improve patients’ QOL [10–12]. The meta-analysis demonstrated strong rigor, using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [13]. Multiple electronic databases were accessed and additional evidence was obtained by review of the retrieved article reference lists. No language limitations were placed on the search, adding to the potential generalizability of the results. The procedures to extract data and evaluate the quality of each retrieved article are detailed providing evidence of the rigor of the authors’ methodology.

The limitations of the meta-analysis are related to the difficulties extracting data from multiple studies without consistent reporting of exercise mode, duration or evaluation methods. Inconsistent CRF assessment methods across studies limits the validity of the results quantifying the magnitude of CRF change identified. Despite the limitations, this is the first known meta-analysis of the effect of exercise on CRF during and after treatment synthesizing current research to provide clinical reccomendations.

As with all exercise prescriptions for any patient, the patient’s level of adherence is a moderating factor for its effectiveness. A recent study describes an interesting exercise intervention that utilizes a resource some cancer patients may already have in their homes. Seven patients with early-stage non-small cell lung cancer performed light-intensity walking and balance exercises in a virtual reality environment with the Nintendo Wii Fit Plus for 6 weeks after thora-cotomy [14]. Exercise started the first week after hospitalization and continued for 6 weeks. Outcomes seen included a decrease in CRF severity, a high level of satisfaction, high adherence rate, and an increase in self-efficacy for managing their CRF [14]. While the small sample size and homogeneous cancer diagnosis and stage limit generalizability, the study describes a promising approach to supporting patient adherence to exercise.

Applications for Clinical Practice

The results of this meta-analysis support exercise as an effective intervention to decrease CRF in oncology patients during and after treatment. Based on the results, exercise should be prescribed as a nonpharmacologic intervention to decrease CRF. Patients’ adherence to the exercise intervention is needed for effective CRF reduction. Thus, exercise prescription should be tailored to patients individual preferences, abilities, and available resources.

—Fay Wright, MSN, APRN, and Allison Squires, PhD, RN

Study Overview

Objective. To systematically review randomized controlled trials (RCTs) examining the effects of exercise interventions on cancer-related fatigue (CRF) in patients during and after treatment to determine differential effects.

Design. Meta-analysis.

Data. 70 RCTs with a combined sample of 4881 oncology patients during active treatment (eg, chemotherapy, radiation therapy, hormone therapy) or after completion of treatment published before August 2011 that analyzed the effect on CRF of an exercise program compared with a non-exercise control. Excluded from analysis were RCTs that compared exercise with other types of interventions (ie, education, pharmacotherapy, different methods of exercise). 43 studies examined exercise during treatment while 27 studied the effects after treatment.

Measurement. Effect size was calculated to determine the magnitude of the effect of exercise on improving CRF.

Main results. The effect size (Δ = 0.34, P < 0.001) for the total sample of 70 RCTs indicated that exercise has a moderate effect on CRF regardless of treatment status. When effect sizes were calculated for the 43 RCTs that examined patients during treatment, exercise was found to significantly decrease CRF (Δ = 0.32, P < 0.001). Based on calculated effect size for the 27 RCTs that examined exercise after treatment completion, exercise continues to significantly decrease CRF (Δ = 0.38, P < 0.001). The effect of exercise on CRF was consistent not only during or after treatment, but also across cancer diagnosis, patient age, and sex.

Exercise reduces CRF both during and after treatment. In patients who exercise, CRF severity decreases by 4.9% compared to a 29.1% increase in CRF in patients who do not exercise. After treatment, exercise decreases CRF by 20.5% compared to a decrease of 1.3% in patients who do not exercise.

Both during and after treatment, patients with higher exercise adherence experienced the most improvement (P < 0.001). Patients in active treatment with less severe baseline CRF demonstrated greater adherence to the exercise program and saw greater improvements in CRF. Patients who were further from active treatment saw greater CRF severity reduction than patients closer to active treatment. After treatment, the longer the exercise program, the more effective it was in decreasing CRF. No specific type of exercise program (eg, home-based, supervised, vigorous, moderate) was shown to be more effective than another.

Conclusion. Exercise decreases CRF in patients during and after treatment. The type of exercise does not change the positive effect of exercise, so it is important to encourage patients to be active.

Commentary

Cancer-related fatigue (CRF) is the most disturbing symptom associated with cancer diagnosis and its treatment [1]. Defined as a persistent, subjective sense of tiredness that is not proportional to activity and not relieved by rest, CRF is reported in over 80% of oncology patients during active treatment [1]. This symptom is not limited to the active treatment phase, with over 30% of cancer survivors reporting CRF lasting at least 5 years [2]. CRF is associated with decreased quality of life (QOL), decreased functional status, and decreased participation in social activities [1]. The pathogenesis of CRF is not fully understood [3,4]. Disruptions in biochemical pathways [5], genome expression [6] chemotherapy or radiation treatments [7,8], cancer pathogenesis [4], or a combination of factors [9] are hypothesized as contributing to the development and severity of CRF. The complexity of CRF pathogenesis makes clinical management difficult.

The current meta-analysis suggests that exercise is an effective nonpharmacologic intervention to ameliorate the impact of this devastating symptom and improve patients’ QOL [10–12]. The meta-analysis demonstrated strong rigor, using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [13]. Multiple electronic databases were accessed and additional evidence was obtained by review of the retrieved article reference lists. No language limitations were placed on the search, adding to the potential generalizability of the results. The procedures to extract data and evaluate the quality of each retrieved article are detailed providing evidence of the rigor of the authors’ methodology.

The limitations of the meta-analysis are related to the difficulties extracting data from multiple studies without consistent reporting of exercise mode, duration or evaluation methods. Inconsistent CRF assessment methods across studies limits the validity of the results quantifying the magnitude of CRF change identified. Despite the limitations, this is the first known meta-analysis of the effect of exercise on CRF during and after treatment synthesizing current research to provide clinical reccomendations.

As with all exercise prescriptions for any patient, the patient’s level of adherence is a moderating factor for its effectiveness. A recent study describes an interesting exercise intervention that utilizes a resource some cancer patients may already have in their homes. Seven patients with early-stage non-small cell lung cancer performed light-intensity walking and balance exercises in a virtual reality environment with the Nintendo Wii Fit Plus for 6 weeks after thora-cotomy [14]. Exercise started the first week after hospitalization and continued for 6 weeks. Outcomes seen included a decrease in CRF severity, a high level of satisfaction, high adherence rate, and an increase in self-efficacy for managing their CRF [14]. While the small sample size and homogeneous cancer diagnosis and stage limit generalizability, the study describes a promising approach to supporting patient adherence to exercise.

Applications for Clinical Practice

The results of this meta-analysis support exercise as an effective intervention to decrease CRF in oncology patients during and after treatment. Based on the results, exercise should be prescribed as a nonpharmacologic intervention to decrease CRF. Patients’ adherence to the exercise intervention is needed for effective CRF reduction. Thus, exercise prescription should be tailored to patients individual preferences, abilities, and available resources.

—Fay Wright, MSN, APRN, and Allison Squires, PhD, RN

Study Overview

Objective. To systematically review randomized controlled trials (RCTs) examining the effects of exercise interventions on cancer-related fatigue (CRF) in patients during and after treatment to determine differential effects.

Design. Meta-analysis.

Data. 70 RCTs with a combined sample of 4881 oncology patients during active treatment (eg, chemotherapy, radiation therapy, hormone therapy) or after completion of treatment published before August 2011 that analyzed the effect on CRF of an exercise program compared with a non-exercise control. Excluded from analysis were RCTs that compared exercise with other types of interventions (ie, education, pharmacotherapy, different methods of exercise). 43 studies examined exercise during treatment while 27 studied the effects after treatment.

Measurement. Effect size was calculated to determine the magnitude of the effect of exercise on improving CRF.

Main results. The effect size (Δ = 0.34, P < 0.001) for the total sample of 70 RCTs indicated that exercise has a moderate effect on CRF regardless of treatment status. When effect sizes were calculated for the 43 RCTs that examined patients during treatment, exercise was found to significantly decrease CRF (Δ = 0.32, P < 0.001). Based on calculated effect size for the 27 RCTs that examined exercise after treatment completion, exercise continues to significantly decrease CRF (Δ = 0.38, P < 0.001). The effect of exercise on CRF was consistent not only during or after treatment, but also across cancer diagnosis, patient age, and sex.

Exercise reduces CRF both during and after treatment. In patients who exercise, CRF severity decreases by 4.9% compared to a 29.1% increase in CRF in patients who do not exercise. After treatment, exercise decreases CRF by 20.5% compared to a decrease of 1.3% in patients who do not exercise.

Both during and after treatment, patients with higher exercise adherence experienced the most improvement (P < 0.001). Patients in active treatment with less severe baseline CRF demonstrated greater adherence to the exercise program and saw greater improvements in CRF. Patients who were further from active treatment saw greater CRF severity reduction than patients closer to active treatment. After treatment, the longer the exercise program, the more effective it was in decreasing CRF. No specific type of exercise program (eg, home-based, supervised, vigorous, moderate) was shown to be more effective than another.

Conclusion. Exercise decreases CRF in patients during and after treatment. The type of exercise does not change the positive effect of exercise, so it is important to encourage patients to be active.

Commentary

Cancer-related fatigue (CRF) is the most disturbing symptom associated with cancer diagnosis and its treatment [1]. Defined as a persistent, subjective sense of tiredness that is not proportional to activity and not relieved by rest, CRF is reported in over 80% of oncology patients during active treatment [1]. This symptom is not limited to the active treatment phase, with over 30% of cancer survivors reporting CRF lasting at least 5 years [2]. CRF is associated with decreased quality of life (QOL), decreased functional status, and decreased participation in social activities [1]. The pathogenesis of CRF is not fully understood [3,4]. Disruptions in biochemical pathways [5], genome expression [6] chemotherapy or radiation treatments [7,8], cancer pathogenesis [4], or a combination of factors [9] are hypothesized as contributing to the development and severity of CRF. The complexity of CRF pathogenesis makes clinical management difficult.

The current meta-analysis suggests that exercise is an effective nonpharmacologic intervention to ameliorate the impact of this devastating symptom and improve patients’ QOL [10–12]. The meta-analysis demonstrated strong rigor, using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [13]. Multiple electronic databases were accessed and additional evidence was obtained by review of the retrieved article reference lists. No language limitations were placed on the search, adding to the potential generalizability of the results. The procedures to extract data and evaluate the quality of each retrieved article are detailed providing evidence of the rigor of the authors’ methodology.

The limitations of the meta-analysis are related to the difficulties extracting data from multiple studies without consistent reporting of exercise mode, duration or evaluation methods. Inconsistent CRF assessment methods across studies limits the validity of the results quantifying the magnitude of CRF change identified. Despite the limitations, this is the first known meta-analysis of the effect of exercise on CRF during and after treatment synthesizing current research to provide clinical reccomendations.

As with all exercise prescriptions for any patient, the patient’s level of adherence is a moderating factor for its effectiveness. A recent study describes an interesting exercise intervention that utilizes a resource some cancer patients may already have in their homes. Seven patients with early-stage non-small cell lung cancer performed light-intensity walking and balance exercises in a virtual reality environment with the Nintendo Wii Fit Plus for 6 weeks after thora-cotomy [14]. Exercise started the first week after hospitalization and continued for 6 weeks. Outcomes seen included a decrease in CRF severity, a high level of satisfaction, high adherence rate, and an increase in self-efficacy for managing their CRF [14]. While the small sample size and homogeneous cancer diagnosis and stage limit generalizability, the study describes a promising approach to supporting patient adherence to exercise.

Applications for Clinical Practice

The results of this meta-analysis support exercise as an effective intervention to decrease CRF in oncology patients during and after treatment. Based on the results, exercise should be prescribed as a nonpharmacologic intervention to decrease CRF. Patients’ adherence to the exercise intervention is needed for effective CRF reduction. Thus, exercise prescription should be tailored to patients individual preferences, abilities, and available resources.

—Fay Wright, MSN, APRN, and Allison Squires, PhD, RN

Study Overview

Objective. To examine changes in adverse event rates among Medicare patients with common medical conditions and conditions requiring surgery hospitalized in acute care hospitals.

Design. Retrospective review utilizing the Medicare Patient Safety Monitoring System (MPSMS) [1], a large database of information abstracted from medical records of a random sample of hospitalized patients in the United States. The database was established in by the Centers for Medicare and Medicaid Services in 2001 to track adverse events in hospitals among Medicare patients, with data collected from every year thereafter except for 2008. The MPSMS tracks 21 indicators of safety that can be reliably abstracted from medical records. Among these are inpatients falls, hospital-acquired pressure ulcers, catheter-associated urinary tract infections, selected hospital-acquired infections, selected adverse events related to high-risk medications, operative events and postoperative events for certain conditions.

Setting and participants. Medicare patients aged 65 and older who had been hospitalized for acute myocardial infarction, congestive heart failure, pneumonia, or conditions requiring surgery from 2005 to 2007 and 2009 to 2011. A total of 61,523 patients were included in the final study sample—11,399 with acute myocardial infarction, 15,374 with congestive heart failure, 18,269 with pneumonia, and 16,481 with conditions requiring surgery from a total of 4372 hospitals.

Main outcome measures. The rate of occurrence of adverse events for which patients were at risk, the proportion of patients with 1 or more adverse events, and the number of adverse events per 1000 hospitalizations.

Statistical analysis. Outcome rates were described and reported in 2-year intervals: 2005–2006, 2007–2009, and 2010–2011. Trends in the number of adverse events per 1000 hospitalizations were modeled using a linear mixed-effects model with Poisson link function. Other composite outcomes were also modeled using linear mixed models for trend analysis.

Main results. Adverse event rates among patients with myocardial infarction and congestive heart failure declined significantly. Among patients with myocardial infarction, rate of adverse event among patients at risk for events declined from 5% to 3.7% (rate difference 1.3%; 95% confidence interval [CI], 0.7 to 1.9) and among patients with congestive heart failure, the rate declined from 3.7% to 2.7% (rate difference 1%; 95% CI, 0.5 to 1.4). Proportion of patients with 1 or more adverse events declined by 6.6% (95% CI, 3.3 to 10.2) among patients with myocardial infarction, and 3.3% (95% CI, 1.0 to 5.5) among patients with congestive heart failure. Number of adverse events per 1000 hospitalizations also declined by 139.7 among patients with myocardial infarction and by 68.3 among patients with congestive heart failure. On the other hand, among patients admitted for pneumonia or for conditions requiring surgery, adverse events rates remained the same. Rate of adverse events among patients admitted for pneumonia remained the same at 3.4% in 2005–2006 and 3.5% in 2010–2011; and for patients admitted for conditions requiring surgery, rate of adverse events remained the same at 3.2% in 2005–2006 and 3.3% in 2010–2011. Similarly, proportion of patients with 1 or more events in the hospital also remained the same in patients with pneumonia (a proportion of 17.1% in 2005–2006 and 17.5% in 2010–11) and conditions requiring surgery (a proportion of 21.6% in 2005–2006 and 22.7% in 2010–2011). Number of events per 1000 hospitalizations also did not change over time. When accounting for patient characteristics and geographic differences in the models, the results also did not substantially change.

Conclusions. In a large nationally representative sample of older adults aged 65 and above, adverse event rates declined among patients admitted for cardiac conditions, including myocardial infarction and congestive heart failure, but did not decline among patients admitted for other medical (pneumonia) or surgical conditions.

Commentary

Patient safety in inpatient hospital care is of paramount importance, and the Affordable Care Act has placed significant emphasis on improving patient safety by aligning incentives and disincentives with patient outcomes on the hospital level [2,3].These measures, including adverse event rates, are reported publicly in reports such as Hospital Compare [3–5].The current study reports on the recent national trends in safety and adverse events using data abstracted from medical records among older Medicare patients with 4 common conditions. The demonstration of the trends in adverse events represent an important first step towards understanding the current environment and trends in patient safety.  The finding that in-hospital adverse event rates have improved in patients admitted for cardiac conditions is reassuring  given that there were substantial nationwide efforts in promoting patient safety in hospitals, but the lack of progress in other conditions both medical and surgical is rather disappointing.

There is good quality evidence suggesting how hospitals may make changes to improve patient safety; these steps may include adopting care practices and protocols such as pressure ulcer monitoring and prevention protocols, fall prevention protocols, safety checklists, models for older adults inpatient care such as Mobile Acute Care of Elderly teams [6] and Acute Care for the Elderly models [7], quality improvement initiatives, and incorporation of information systems for data tracking and reporting, to name a few. How hospitals adopt different practices for the care of patients with different conditions may explain the study findings. The challenge is to figure out why noncardiac conditions do not have improving trends in patient safety and to demonstrate what works (and what doesn’t) on the hospital level. Understanding how care is delivered on the hospital level and correlating hospital level practices with patient outcomes from databases such as MPSMS may yield clues as to what specific steps hospitals have taken that have yielded changes in patient safety.

Applications for Clinical Practice

This study highlights trends in adverse events among hospitalized older adults that demonstrated improvements for patients with cardiac conditions but not for others. Future studies need to focus on understanding what works and what doesn’t so that hospitals can adopt safety practices that improve outcomes for older hospitalized patients.

—William Hung, MD, MPH

Study Overview

Objective. To examine changes in adverse event rates among Medicare patients with common medical conditions and conditions requiring surgery hospitalized in acute care hospitals.

Design. Retrospective review utilizing the Medicare Patient Safety Monitoring System (MPSMS) [1], a large database of information abstracted from medical records of a random sample of hospitalized patients in the United States. The database was established in by the Centers for Medicare and Medicaid Services in 2001 to track adverse events in hospitals among Medicare patients, with data collected from every year thereafter except for 2008. The MPSMS tracks 21 indicators of safety that can be reliably abstracted from medical records. Among these are inpatients falls, hospital-acquired pressure ulcers, catheter-associated urinary tract infections, selected hospital-acquired infections, selected adverse events related to high-risk medications, operative events and postoperative events for certain conditions.

Setting and participants. Medicare patients aged 65 and older who had been hospitalized for acute myocardial infarction, congestive heart failure, pneumonia, or conditions requiring surgery from 2005 to 2007 and 2009 to 2011. A total of 61,523 patients were included in the final study sample—11,399 with acute myocardial infarction, 15,374 with congestive heart failure, 18,269 with pneumonia, and 16,481 with conditions requiring surgery from a total of 4372 hospitals.

Main outcome measures. The rate of occurrence of adverse events for which patients were at risk, the proportion of patients with 1 or more adverse events, and the number of adverse events per 1000 hospitalizations.

Statistical analysis. Outcome rates were described and reported in 2-year intervals: 2005–2006, 2007–2009, and 2010–2011. Trends in the number of adverse events per 1000 hospitalizations were modeled using a linear mixed-effects model with Poisson link function. Other composite outcomes were also modeled using linear mixed models for trend analysis.

Main results. Adverse event rates among patients with myocardial infarction and congestive heart failure declined significantly. Among patients with myocardial infarction, rate of adverse event among patients at risk for events declined from 5% to 3.7% (rate difference 1.3%; 95% confidence interval [CI], 0.7 to 1.9) and among patients with congestive heart failure, the rate declined from 3.7% to 2.7% (rate difference 1%; 95% CI, 0.5 to 1.4). Proportion of patients with 1 or more adverse events declined by 6.6% (95% CI, 3.3 to 10.2) among patients with myocardial infarction, and 3.3% (95% CI, 1.0 to 5.5) among patients with congestive heart failure. Number of adverse events per 1000 hospitalizations also declined by 139.7 among patients with myocardial infarction and by 68.3 among patients with congestive heart failure. On the other hand, among patients admitted for pneumonia or for conditions requiring surgery, adverse events rates remained the same. Rate of adverse events among patients admitted for pneumonia remained the same at 3.4% in 2005–2006 and 3.5% in 2010–2011; and for patients admitted for conditions requiring surgery, rate of adverse events remained the same at 3.2% in 2005–2006 and 3.3% in 2010–2011. Similarly, proportion of patients with 1 or more events in the hospital also remained the same in patients with pneumonia (a proportion of 17.1% in 2005–2006 and 17.5% in 2010–11) and conditions requiring surgery (a proportion of 21.6% in 2005–2006 and 22.7% in 2010–2011). Number of events per 1000 hospitalizations also did not change over time. When accounting for patient characteristics and geographic differences in the models, the results also did not substantially change.

Conclusions. In a large nationally representative sample of older adults aged 65 and above, adverse event rates declined among patients admitted for cardiac conditions, including myocardial infarction and congestive heart failure, but did not decline among patients admitted for other medical (pneumonia) or surgical conditions.

Commentary

Patient safety in inpatient hospital care is of paramount importance, and the Affordable Care Act has placed significant emphasis on improving patient safety by aligning incentives and disincentives with patient outcomes on the hospital level [2,3].These measures, including adverse event rates, are reported publicly in reports such as Hospital Compare [3–5].The current study reports on the recent national trends in safety and adverse events using data abstracted from medical records among older Medicare patients with 4 common conditions. The demonstration of the trends in adverse events represent an important first step towards understanding the current environment and trends in patient safety.  The finding that in-hospital adverse event rates have improved in patients admitted for cardiac conditions is reassuring  given that there were substantial nationwide efforts in promoting patient safety in hospitals, but the lack of progress in other conditions both medical and surgical is rather disappointing.

There is good quality evidence suggesting how hospitals may make changes to improve patient safety; these steps may include adopting care practices and protocols such as pressure ulcer monitoring and prevention protocols, fall prevention protocols, safety checklists, models for older adults inpatient care such as Mobile Acute Care of Elderly teams [6] and Acute Care for the Elderly models [7], quality improvement initiatives, and incorporation of information systems for data tracking and reporting, to name a few. How hospitals adopt different practices for the care of patients with different conditions may explain the study findings. The challenge is to figure out why noncardiac conditions do not have improving trends in patient safety and to demonstrate what works (and what doesn’t) on the hospital level. Understanding how care is delivered on the hospital level and correlating hospital level practices with patient outcomes from databases such as MPSMS may yield clues as to what specific steps hospitals have taken that have yielded changes in patient safety.

Applications for Clinical Practice

This study highlights trends in adverse events among hospitalized older adults that demonstrated improvements for patients with cardiac conditions but not for others. Future studies need to focus on understanding what works and what doesn’t so that hospitals can adopt safety practices that improve outcomes for older hospitalized patients.

—William Hung, MD, MPH

Study Overview

Objective. To examine changes in adverse event rates among Medicare patients with common medical conditions and conditions requiring surgery hospitalized in acute care hospitals.

Design. Retrospective review utilizing the Medicare Patient Safety Monitoring System (MPSMS) [1], a large database of information abstracted from medical records of a random sample of hospitalized patients in the United States. The database was established in by the Centers for Medicare and Medicaid Services in 2001 to track adverse events in hospitals among Medicare patients, with data collected from every year thereafter except for 2008. The MPSMS tracks 21 indicators of safety that can be reliably abstracted from medical records. Among these are inpatients falls, hospital-acquired pressure ulcers, catheter-associated urinary tract infections, selected hospital-acquired infections, selected adverse events related to high-risk medications, operative events and postoperative events for certain conditions.

Setting and participants. Medicare patients aged 65 and older who had been hospitalized for acute myocardial infarction, congestive heart failure, pneumonia, or conditions requiring surgery from 2005 to 2007 and 2009 to 2011. A total of 61,523 patients were included in the final study sample—11,399 with acute myocardial infarction, 15,374 with congestive heart failure, 18,269 with pneumonia, and 16,481 with conditions requiring surgery from a total of 4372 hospitals.

Main outcome measures. The rate of occurrence of adverse events for which patients were at risk, the proportion of patients with 1 or more adverse events, and the number of adverse events per 1000 hospitalizations.

Statistical analysis. Outcome rates were described and reported in 2-year intervals: 2005–2006, 2007–2009, and 2010–2011. Trends in the number of adverse events per 1000 hospitalizations were modeled using a linear mixed-effects model with Poisson link function. Other composite outcomes were also modeled using linear mixed models for trend analysis.

Main results. Adverse event rates among patients with myocardial infarction and congestive heart failure declined significantly. Among patients with myocardial infarction, rate of adverse event among patients at risk for events declined from 5% to 3.7% (rate difference 1.3%; 95% confidence interval [CI], 0.7 to 1.9) and among patients with congestive heart failure, the rate declined from 3.7% to 2.7% (rate difference 1%; 95% CI, 0.5 to 1.4). Proportion of patients with 1 or more adverse events declined by 6.6% (95% CI, 3.3 to 10.2) among patients with myocardial infarction, and 3.3% (95% CI, 1.0 to 5.5) among patients with congestive heart failure. Number of adverse events per 1000 hospitalizations also declined by 139.7 among patients with myocardial infarction and by 68.3 among patients with congestive heart failure. On the other hand, among patients admitted for pneumonia or for conditions requiring surgery, adverse events rates remained the same. Rate of adverse events among patients admitted for pneumonia remained the same at 3.4% in 2005–2006 and 3.5% in 2010–2011; and for patients admitted for conditions requiring surgery, rate of adverse events remained the same at 3.2% in 2005–2006 and 3.3% in 2010–2011. Similarly, proportion of patients with 1 or more events in the hospital also remained the same in patients with pneumonia (a proportion of 17.1% in 2005–2006 and 17.5% in 2010–11) and conditions requiring surgery (a proportion of 21.6% in 2005–2006 and 22.7% in 2010–2011). Number of events per 1000 hospitalizations also did not change over time. When accounting for patient characteristics and geographic differences in the models, the results also did not substantially change.

Conclusions. In a large nationally representative sample of older adults aged 65 and above, adverse event rates declined among patients admitted for cardiac conditions, including myocardial infarction and congestive heart failure, but did not decline among patients admitted for other medical (pneumonia) or surgical conditions.

Commentary

Patient safety in inpatient hospital care is of paramount importance, and the Affordable Care Act has placed significant emphasis on improving patient safety by aligning incentives and disincentives with patient outcomes on the hospital level [2,3].These measures, including adverse event rates, are reported publicly in reports such as Hospital Compare [3–5].The current study reports on the recent national trends in safety and adverse events using data abstracted from medical records among older Medicare patients with 4 common conditions. The demonstration of the trends in adverse events represent an important first step towards understanding the current environment and trends in patient safety.  The finding that in-hospital adverse event rates have improved in patients admitted for cardiac conditions is reassuring  given that there were substantial nationwide efforts in promoting patient safety in hospitals, but the lack of progress in other conditions both medical and surgical is rather disappointing.

There is good quality evidence suggesting how hospitals may make changes to improve patient safety; these steps may include adopting care practices and protocols such as pressure ulcer monitoring and prevention protocols, fall prevention protocols, safety checklists, models for older adults inpatient care such as Mobile Acute Care of Elderly teams [6] and Acute Care for the Elderly models [7], quality improvement initiatives, and incorporation of information systems for data tracking and reporting, to name a few. How hospitals adopt different practices for the care of patients with different conditions may explain the study findings. The challenge is to figure out why noncardiac conditions do not have improving trends in patient safety and to demonstrate what works (and what doesn’t) on the hospital level. Understanding how care is delivered on the hospital level and correlating hospital level practices with patient outcomes from databases such as MPSMS may yield clues as to what specific steps hospitals have taken that have yielded changes in patient safety.

Applications for Clinical Practice

This study highlights trends in adverse events among hospitalized older adults that demonstrated improvements for patients with cardiac conditions but not for others. Future studies need to focus on understanding what works and what doesn’t so that hospitals can adopt safety practices that improve outcomes for older hospitalized patients.

—William Hung, MD, MPH

Study Overview

Objective. To compare radiofrequency ablation (RFA) with antiarrhythmic drugs in treating patients with paroxysmal atrial fibrillation as a first-line therapy.

Design. Randomized controlled trial.

Setting and participants. This multi-center study was conducted at 16 sites in 5 countries and enrolled 127 patients between July 2006 and January 2010. Adult patients < 75 years old with a history of paroxysmal atrial fibrillation who had at least 1 episode of symptomatic paroxysmal atrial fibrillation in the 6 months prior to enrollment and had no previous antiarrhythmic drug treatment were recruited. Patients were excluded if they had structural heart disease or had a complete contraindication for the use of heparin, warfarin, or both.

Patients were randomized by variable block generated by computer to receive either antiarrhythmic drugs or RFA. All patients were followed up at 1, 3, 6, 12, and 24 months after randomization. Each patient received a transtelephonic monitor system and was trained to record and transmit symptomatic episodes of possible atrial fibrillation. Patients were also instructed to transmit biweekly recordings on a Friday, regardless of whether they had experienced symptoms. Blinded experienced electrophysiologists analyzed all recordings, which may also have included scheduled or unscheduled electrocardiogram, Holter, or rhythm strips.

Patients randomized to the antiarrhythmic drug group were administered medications chosen by the investigators. Drug dosages titrated during the 90-day blanking period were maintained throughout the study. Patients in the antiarrhythmic drug group were also allowed to cross over and undergo ablation after 90 days if medical treatment had failed.

Patients randomized to the RFA group underwent circumferential isolation of the pulmonary veins. Additional ablation lesions were also allowed at investigator’s choice. Furthermore, selections of the ablation catheter, power and irrigation settings, as well as the use of navigation systems were left to the discretion of the investigator. Following RFA, anticoagulation with warfarin was maintained for at least 3 months.

Main outcome measures. The primary outcome was time to first recurrence of symptomatic or asymptomatic atrial fibrillation, atrial flutter, or atrial tachycardia lasting more than 30 seconds. Secondary outcomes were symptomatic recurrences of atrial fibrillation, atrial flutter, or atrial tachycardia during the study period and quality of life as measured by EQ-5D Tariff score. There was a 90-day blanking period (the time after randomization when an AF event is not counted).

Main results. The RFA group experienced a significantly lower rate of recurrence of atrial tachyarrhythmias at 2 years compared with the antiarrhythmic drug group (54.5% vs. 72.1%, hazard ratio [HR] 0.56 [95% CI, 0.35–0.90]; P = 0.02). The difference was present but smaller for the rate of symptomatic arrhythmias (47% RFA group vs. 59% drug therapy group, HR 0.56 [95% CI, 0.33–0.95]; P = 0.03). There were no differences among treatment groups in regard to quality of life at 1-year follow-up using the EQ-5D Tariff score. No deaths or strokes reported in either group; 4 cases (6%) of cardiac tampoade were reported in the RFA group.

Conclusion. The authors of this study conclude that for paroxysmal atrial fibrillation patients without previous antiarrhythmic drug treatment, RFA resulted in a lower rate of recurrence of atrial tachyarrhythmias at 2 years compared with standard antiarrhythmic drug treatment. However, recurrence was frequent in both groups after 2 years.

Commentary

Atrial fibrillation is a common arrhythmia associated with an increased risk of stroke and other adverse events. Current practice guidelines recommend antiarrhythmic drugs as the first-line therapy for patients with symptomatic paroxysmal atrial fibrillation. However, a significant proportion of patients are nonadherent with antiarrhythmic therapy. As a result, antiarrhythmic therapy is only 46% effective at 12 months in preventing the recurrence of atrial fibrillation [1].

The purpose of the current study (Radiofrequency Ablation vs. Antiarrhythmic Drugs for Atrial Fibrillation Treatment-2, or RAAFT-2) was to determine whether RFA is superior to antiarrhythmic drugs as first-line therapy in patients with paroxysmal atrial fibrillation who had not been exposed to antiarrhythmic treatment. Over the past decade, various single-center trials attempted to demonstrate the superiority of RAF. Evidence from these trials suggested that RFA resulted in lower burden of atrial fibrillation and more patients free from atrial fibrillation. However, RFA had a higher initial cost, higher rate of complications, and conferred no improvement in the quality of life [2–5].

Despite the statistically significant lower rate of recurrence of atrial tachyarrhythmias in the RFA group, there are many limitations with this multi-center, multi-country study. First, selection bias may have been present, as it took 42 months to recruit 127 patients in 16 centers and 5 countries for a very common disease. Second, the use of a transtelephonic monitor was unique. When the investigators excluded transtelephonic monitor results and used electrocardiogram and Holter monitor results, similar to previous trials, the primary outcomes were no longer different. Third, biases in the study design favor RFA. For example, investigators permitted substantial variation in the RFA procedures but restricted dosage changes in the antiarrhythmic drugs group. Finally, 26 of the 61 patients (42.6%) assigned to the antiarrhythmic drug group crossed over to undergo RFA, and the intention-to-treat basis became invalid.

One might ask, what is the worth of this trial? This trial provides additional evidence about about the risks of RFA. While no deaths or strokes were reported in this trial, 6 of the 66 patients (9.1%) in the RFA group had a serious adverse event, with 4 patients (6%)  experiencing pericardial effusion with tamponade. The 6% tamponade rate is similar to that found in previous trials [2]. On the other hand, only 3 of the 61 patients (4.9%) in the antiarrhythmic drugs group experienced a serious adverse event (1 had atrial flutter with 1:1 atrioventricular conduction, 2 had syncope).

Applications for Clinical Practice

This trial of radiofrequency ablation vs. antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation provides further evidence of the risks and benefits of each of these options. The current guidelines should be followed. However, given the high level of medical therapy noncompliance, selected patients should also be given the option of using RFA as primary treatment. Patients who are offered the procedure should be made aware of the risks, and providers should  incorporate patient’s risk perceptions and preferences in treatment planning.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To compare radiofrequency ablation (RFA) with antiarrhythmic drugs in treating patients with paroxysmal atrial fibrillation as a first-line therapy.

Design. Randomized controlled trial.

Setting and participants. This multi-center study was conducted at 16 sites in 5 countries and enrolled 127 patients between July 2006 and January 2010. Adult patients < 75 years old with a history of paroxysmal atrial fibrillation who had at least 1 episode of symptomatic paroxysmal atrial fibrillation in the 6 months prior to enrollment and had no previous antiarrhythmic drug treatment were recruited. Patients were excluded if they had structural heart disease or had a complete contraindication for the use of heparin, warfarin, or both.

Patients were randomized by variable block generated by computer to receive either antiarrhythmic drugs or RFA. All patients were followed up at 1, 3, 6, 12, and 24 months after randomization. Each patient received a transtelephonic monitor system and was trained to record and transmit symptomatic episodes of possible atrial fibrillation. Patients were also instructed to transmit biweekly recordings on a Friday, regardless of whether they had experienced symptoms. Blinded experienced electrophysiologists analyzed all recordings, which may also have included scheduled or unscheduled electrocardiogram, Holter, or rhythm strips.

Patients randomized to the antiarrhythmic drug group were administered medications chosen by the investigators. Drug dosages titrated during the 90-day blanking period were maintained throughout the study. Patients in the antiarrhythmic drug group were also allowed to cross over and undergo ablation after 90 days if medical treatment had failed.

Patients randomized to the RFA group underwent circumferential isolation of the pulmonary veins. Additional ablation lesions were also allowed at investigator’s choice. Furthermore, selections of the ablation catheter, power and irrigation settings, as well as the use of navigation systems were left to the discretion of the investigator. Following RFA, anticoagulation with warfarin was maintained for at least 3 months.

Main outcome measures. The primary outcome was time to first recurrence of symptomatic or asymptomatic atrial fibrillation, atrial flutter, or atrial tachycardia lasting more than 30 seconds. Secondary outcomes were symptomatic recurrences of atrial fibrillation, atrial flutter, or atrial tachycardia during the study period and quality of life as measured by EQ-5D Tariff score. There was a 90-day blanking period (the time after randomization when an AF event is not counted).

Main results. The RFA group experienced a significantly lower rate of recurrence of atrial tachyarrhythmias at 2 years compared with the antiarrhythmic drug group (54.5% vs. 72.1%, hazard ratio [HR] 0.56 [95% CI, 0.35–0.90]; P = 0.02). The difference was present but smaller for the rate of symptomatic arrhythmias (47% RFA group vs. 59% drug therapy group, HR 0.56 [95% CI, 0.33–0.95]; P = 0.03). There were no differences among treatment groups in regard to quality of life at 1-year follow-up using the EQ-5D Tariff score. No deaths or strokes reported in either group; 4 cases (6%) of cardiac tampoade were reported in the RFA group.

Conclusion. The authors of this study conclude that for paroxysmal atrial fibrillation patients without previous antiarrhythmic drug treatment, RFA resulted in a lower rate of recurrence of atrial tachyarrhythmias at 2 years compared with standard antiarrhythmic drug treatment. However, recurrence was frequent in both groups after 2 years.

Commentary

Atrial fibrillation is a common arrhythmia associated with an increased risk of stroke and other adverse events. Current practice guidelines recommend antiarrhythmic drugs as the first-line therapy for patients with symptomatic paroxysmal atrial fibrillation. However, a significant proportion of patients are nonadherent with antiarrhythmic therapy. As a result, antiarrhythmic therapy is only 46% effective at 12 months in preventing the recurrence of atrial fibrillation [1].

The purpose of the current study (Radiofrequency Ablation vs. Antiarrhythmic Drugs for Atrial Fibrillation Treatment-2, or RAAFT-2) was to determine whether RFA is superior to antiarrhythmic drugs as first-line therapy in patients with paroxysmal atrial fibrillation who had not been exposed to antiarrhythmic treatment. Over the past decade, various single-center trials attempted to demonstrate the superiority of RAF. Evidence from these trials suggested that RFA resulted in lower burden of atrial fibrillation and more patients free from atrial fibrillation. However, RFA had a higher initial cost, higher rate of complications, and conferred no improvement in the quality of life [2–5].

Despite the statistically significant lower rate of recurrence of atrial tachyarrhythmias in the RFA group, there are many limitations with this multi-center, multi-country study. First, selection bias may have been present, as it took 42 months to recruit 127 patients in 16 centers and 5 countries for a very common disease. Second, the use of a transtelephonic monitor was unique. When the investigators excluded transtelephonic monitor results and used electrocardiogram and Holter monitor results, similar to previous trials, the primary outcomes were no longer different. Third, biases in the study design favor RFA. For example, investigators permitted substantial variation in the RFA procedures but restricted dosage changes in the antiarrhythmic drugs group. Finally, 26 of the 61 patients (42.6%) assigned to the antiarrhythmic drug group crossed over to undergo RFA, and the intention-to-treat basis became invalid.

One might ask, what is the worth of this trial? This trial provides additional evidence about about the risks of RFA. While no deaths or strokes were reported in this trial, 6 of the 66 patients (9.1%) in the RFA group had a serious adverse event, with 4 patients (6%)  experiencing pericardial effusion with tamponade. The 6% tamponade rate is similar to that found in previous trials [2]. On the other hand, only 3 of the 61 patients (4.9%) in the antiarrhythmic drugs group experienced a serious adverse event (1 had atrial flutter with 1:1 atrioventricular conduction, 2 had syncope).

Applications for Clinical Practice

This trial of radiofrequency ablation vs. antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation provides further evidence of the risks and benefits of each of these options. The current guidelines should be followed. However, given the high level of medical therapy noncompliance, selected patients should also be given the option of using RFA as primary treatment. Patients who are offered the procedure should be made aware of the risks, and providers should  incorporate patient’s risk perceptions and preferences in treatment planning.

—Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To compare radiofrequency ablation (RFA) with antiarrhythmic drugs in treating patients with paroxysmal atrial fibrillation as a first-line therapy.

Design. Randomized controlled trial.

Setting and participants. This multi-center study was conducted at 16 sites in 5 countries and enrolled 127 patients between July 2006 and January 2010. Adult patients < 75 years old with a history of paroxysmal atrial fibrillation who had at least 1 episode of symptomatic paroxysmal atrial fibrillation in the 6 months prior to enrollment and had no previous antiarrhythmic drug treatment were recruited. Patients were excluded if they had structural heart disease or had a complete contraindication for the use of heparin, warfarin, or both.

Patients were randomized by variable block generated by computer to receive either antiarrhythmic drugs or RFA. All patients were followed up at 1, 3, 6, 12, and 24 months after randomization. Each patient received a transtelephonic monitor system and was trained to record and transmit symptomatic episodes of possible atrial fibrillation. Patients were also instructed to transmit biweekly recordings on a Friday, regardless of whether they had experienced symptoms. Blinded experienced electrophysiologists analyzed all recordings, which may also have included scheduled or unscheduled electrocardiogram, Holter, or rhythm strips.

Patients randomized to the antiarrhythmic drug group were administered medications chosen by the investigators. Drug dosages titrated during the 90-day blanking period were maintained throughout the study. Patients in the antiarrhythmic drug group were also allowed to cross over and undergo ablation after 90 days if medical treatment had failed.

Patients randomized to the RFA group underwent circumferential isolation of the pulmonary veins. Additional ablation lesions were also allowed at investigator’s choice. Furthermore, selections of the ablation catheter, power and irrigation settings, as well as the use of navigation systems were left to the discretion of the investigator. Following RFA, anticoagulation with warfarin was maintained for at least 3 months.

Main outcome measures. The primary outcome was time to first recurrence of symptomatic or asymptomatic atrial fibrillation, atrial flutter, or atrial tachycardia lasting more than 30 seconds. Secondary outcomes were symptomatic recurrences of atrial fibrillation, atrial flutter, or atrial tachycardia during the study period and quality of life as measured by EQ-5D Tariff score. There was a 90-day blanking period (the time after randomization when an AF event is not counted).

Main results. The RFA group experienced a significantly lower rate of recurrence of atrial tachyarrhythmias at 2 years compared with the antiarrhythmic drug group (54.5% vs. 72.1%, hazard ratio [HR] 0.56 [95% CI, 0.35–0.90]; P = 0.02). The difference was present but smaller for the rate of symptomatic arrhythmias (47% RFA group vs. 59% drug therapy group, HR 0.56 [95% CI, 0.33–0.95]; P = 0.03). There were no differences among treatment groups in regard to quality of life at 1-year follow-up using the EQ-5D Tariff score. No deaths or strokes reported in either group; 4 cases (6%) of cardiac tampoade were reported in the RFA group.

Conclusion. The authors of this study conclude that for paroxysmal atrial fibrillation patients without previous antiarrhythmic drug treatment, RFA resulted in a lower rate of recurrence of atrial tachyarrhythmias at 2 years compared with standard antiarrhythmic drug treatment. However, recurrence was frequent in both groups after 2 years.

Commentary

Atrial fibrillation is a common arrhythmia associated with an increased risk of stroke and other adverse events. Current practice guidelines recommend antiarrhythmic drugs as the first-line therapy for patients with symptomatic paroxysmal atrial fibrillation. However, a significant proportion of patients are nonadherent with antiarrhythmic therapy. As a result, antiarrhythmic therapy is only 46% effective at 12 months in preventing the recurrence of atrial fibrillation [1].

The purpose of the current study (Radiofrequency Ablation vs. Antiarrhythmic Drugs for Atrial Fibrillation Treatment-2, or RAAFT-2) was to determine whether RFA is superior to antiarrhythmic drugs as first-line therapy in patients with paroxysmal atrial fibrillation who had not been exposed to antiarrhythmic treatment. Over the past decade, various single-center trials attempted to demonstrate the superiority of RAF. Evidence from these trials suggested that RFA resulted in lower burden of atrial fibrillation and more patients free from atrial fibrillation. However, RFA had a higher initial cost, higher rate of complications, and conferred no improvement in the quality of life [2–5].

Despite the statistically significant lower rate of recurrence of atrial tachyarrhythmias in the RFA group, there are many limitations with this multi-center, multi-country study. First, selection bias may have been present, as it took 42 months to recruit 127 patients in 16 centers and 5 countries for a very common disease. Second, the use of a transtelephonic monitor was unique. When the investigators excluded transtelephonic monitor results and used electrocardiogram and Holter monitor results, similar to previous trials, the primary outcomes were no longer different. Third, biases in the study design favor RFA. For example, investigators permitted substantial variation in the RFA procedures but restricted dosage changes in the antiarrhythmic drugs group. Finally, 26 of the 61 patients (42.6%) assigned to the antiarrhythmic drug group crossed over to undergo RFA, and the intention-to-treat basis became invalid.

One might ask, what is the worth of this trial? This trial provides additional evidence about about the risks of RFA. While no deaths or strokes were reported in this trial, 6 of the 66 patients (9.1%) in the RFA group had a serious adverse event, with 4 patients (6%)  experiencing pericardial effusion with tamponade. The 6% tamponade rate is similar to that found in previous trials [2]. On the other hand, only 3 of the 61 patients (4.9%) in the antiarrhythmic drugs group experienced a serious adverse event (1 had atrial flutter with 1:1 atrioventricular conduction, 2 had syncope).

Applications for Clinical Practice

This trial of radiofrequency ablation vs. antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation provides further evidence of the risks and benefits of each of these options. The current guidelines should be followed. However, given the high level of medical therapy noncompliance, selected patients should also be given the option of using RFA as primary treatment. Patients who are offered the procedure should be made aware of the risks, and providers should  incorporate patient’s risk perceptions and preferences in treatment planning.

—Ka Ming Gordon Ngai, MD, MPH

The Thoracic Surgery Residents Association currently serves as the largest, official representative organization for cardiothoracic surgery trainees in the United States. The mission of the TSRA is to represent the interest of all cardiothoracic surgery residents through the improvement of thoracic surgery education and partnership with the Thoracic Surgery Directors Association (TSDA). Resident membership in the TSRA commences upon enrollment in an Accreditation Council of Graduate Medical Education (ACGME) accredited thoracic surgery residency program and remains until completion of thoracic residency or subsequent advanced fellowship training. The TSRA also provides resident representation directly to several important national organizations, including the American Association for Thoracic Surgery (AATS), Society of Thoracic Surgeons (STS), Joint Council for Thoracic Surgical Education, American Association of Medical Colleges, ACGME, Thoracic Surgery Residency Review Committee, and CTSNet.

The TSRA organizes two exciting resident forums held during the annual AATS and STS meetings. These forums provide direct interaction between residents, invited speakers, and representatives of the AATS, STS, and TSDA. All residents attending the conferences are invited and encouraged to attend and participate.

The TSRA values professional mentorship. Thus, each year, the TSRA formally recognizes surgeons who have made outstanding contributions to cardiothoracic surgery education. The Socrates Award is presented to a surgical educator who has demonstrated a significant commitment to excellence in resident education. The Dr. Dwight C. McGoon Award is presented to an individual who has significantly contributed to the clinical and educational development of thoracic surgery residents through inspiring academic and political contributions to the specialty.

The TSRA has taken leadership in the development of several new and exciting projects designed to facilitate and compliment resident education. Through the contribution of hundreds of different thoracic surgical trainees across the United States, the TSRA has produced a series of resources to assist residents in their training and board preparation. Our flagship project culminated in the publishing of the TSRA Review of Cardiothoracic Surgery, which has now been in circulation for over three years. Available in both print and electronic media, this review source has been utilized by CT residents not only in the United States, but also in several other countries as well. Last spring, the TSRA continued these efforts with the publishing of the 2nd and 3rd installments of our cardiothoracic surgical review series, TSRA Primer of Cardiothoracic Surgery and TSRA Clinical Scenarios in Cardiothoracic Surgery. TSRA Primer is an exciting, multimedia-based resource designed for Junior level CT residents and beginning fellows focused upon enhancing an underlying foundation of basic cardiothoracic surgical knowledge. TSRA Clinical Scenarios provides the first available, comprehensive review designed to assist residents to work through common clinical scenarios encountered in CT training, clinical practice, and on the oral boards.

This spring, the TSRA will launch the new TSRA Operative Dictations in Cardiothoracic Surgery, a review of key operative indications and steps for a variety of adult cardiac, general thoracic, and congenital operations as well example templates to assist in operative dictations, and the TSRA Journal Club, an online resource that offers residents an easily accessible library of seminal and current journal articles in the areas of cardiac, thoracic, and congenital heart surgery.

The TSRA is an entirely resident run organization that strongly encourages the active participation of all CT surgical trainees. To learn more about our organization, visit our webpage (www.tsranet.org) and/or on visit us on Facebook (www.facebook.com/thoracicsurgeryresidentsassociation).

The Thoracic Surgery Residents Association currently serves as the largest, official representative organization for cardiothoracic surgery trainees in the United States. The mission of the TSRA is to represent the interest of all cardiothoracic surgery residents through the improvement of thoracic surgery education and partnership with the Thoracic Surgery Directors Association (TSDA). Resident membership in the TSRA commences upon enrollment in an Accreditation Council of Graduate Medical Education (ACGME) accredited thoracic surgery residency program and remains until completion of thoracic residency or subsequent advanced fellowship training. The TSRA also provides resident representation directly to several important national organizations, including the American Association for Thoracic Surgery (AATS), Society of Thoracic Surgeons (STS), Joint Council for Thoracic Surgical Education, American Association of Medical Colleges, ACGME, Thoracic Surgery Residency Review Committee, and CTSNet.

The TSRA organizes two exciting resident forums held during the annual AATS and STS meetings. These forums provide direct interaction between residents, invited speakers, and representatives of the AATS, STS, and TSDA. All residents attending the conferences are invited and encouraged to attend and participate.

The TSRA values professional mentorship. Thus, each year, the TSRA formally recognizes surgeons who have made outstanding contributions to cardiothoracic surgery education. The Socrates Award is presented to a surgical educator who has demonstrated a significant commitment to excellence in resident education. The Dr. Dwight C. McGoon Award is presented to an individual who has significantly contributed to the clinical and educational development of thoracic surgery residents through inspiring academic and political contributions to the specialty.

The TSRA has taken leadership in the development of several new and exciting projects designed to facilitate and compliment resident education. Through the contribution of hundreds of different thoracic surgical trainees across the United States, the TSRA has produced a series of resources to assist residents in their training and board preparation. Our flagship project culminated in the publishing of the TSRA Review of Cardiothoracic Surgery, which has now been in circulation for over three years. Available in both print and electronic media, this review source has been utilized by CT residents not only in the United States, but also in several other countries as well. Last spring, the TSRA continued these efforts with the publishing of the 2nd and 3rd installments of our cardiothoracic surgical review series, TSRA Primer of Cardiothoracic Surgery and TSRA Clinical Scenarios in Cardiothoracic Surgery. TSRA Primer is an exciting, multimedia-based resource designed for Junior level CT residents and beginning fellows focused upon enhancing an underlying foundation of basic cardiothoracic surgical knowledge. TSRA Clinical Scenarios provides the first available, comprehensive review designed to assist residents to work through common clinical scenarios encountered in CT training, clinical practice, and on the oral boards.

This spring, the TSRA will launch the new TSRA Operative Dictations in Cardiothoracic Surgery, a review of key operative indications and steps for a variety of adult cardiac, general thoracic, and congenital operations as well example templates to assist in operative dictations, and the TSRA Journal Club, an online resource that offers residents an easily accessible library of seminal and current journal articles in the areas of cardiac, thoracic, and congenital heart surgery.

The TSRA is an entirely resident run organization that strongly encourages the active participation of all CT surgical trainees. To learn more about our organization, visit our webpage (www.tsranet.org) and/or on visit us on Facebook (www.facebook.com/thoracicsurgeryresidentsassociation).

The Thoracic Surgery Residents Association currently serves as the largest, official representative organization for cardiothoracic surgery trainees in the United States. The mission of the TSRA is to represent the interest of all cardiothoracic surgery residents through the improvement of thoracic surgery education and partnership with the Thoracic Surgery Directors Association (TSDA). Resident membership in the TSRA commences upon enrollment in an Accreditation Council of Graduate Medical Education (ACGME) accredited thoracic surgery residency program and remains until completion of thoracic residency or subsequent advanced fellowship training. The TSRA also provides resident representation directly to several important national organizations, including the American Association for Thoracic Surgery (AATS), Society of Thoracic Surgeons (STS), Joint Council for Thoracic Surgical Education, American Association of Medical Colleges, ACGME, Thoracic Surgery Residency Review Committee, and CTSNet.

The TSRA organizes two exciting resident forums held during the annual AATS and STS meetings. These forums provide direct interaction between residents, invited speakers, and representatives of the AATS, STS, and TSDA. All residents attending the conferences are invited and encouraged to attend and participate.

The TSRA values professional mentorship. Thus, each year, the TSRA formally recognizes surgeons who have made outstanding contributions to cardiothoracic surgery education. The Socrates Award is presented to a surgical educator who has demonstrated a significant commitment to excellence in resident education. The Dr. Dwight C. McGoon Award is presented to an individual who has significantly contributed to the clinical and educational development of thoracic surgery residents through inspiring academic and political contributions to the specialty.

The TSRA has taken leadership in the development of several new and exciting projects designed to facilitate and compliment resident education. Through the contribution of hundreds of different thoracic surgical trainees across the United States, the TSRA has produced a series of resources to assist residents in their training and board preparation. Our flagship project culminated in the publishing of the TSRA Review of Cardiothoracic Surgery, which has now been in circulation for over three years. Available in both print and electronic media, this review source has been utilized by CT residents not only in the United States, but also in several other countries as well. Last spring, the TSRA continued these efforts with the publishing of the 2nd and 3rd installments of our cardiothoracic surgical review series, TSRA Primer of Cardiothoracic Surgery and TSRA Clinical Scenarios in Cardiothoracic Surgery. TSRA Primer is an exciting, multimedia-based resource designed for Junior level CT residents and beginning fellows focused upon enhancing an underlying foundation of basic cardiothoracic surgical knowledge. TSRA Clinical Scenarios provides the first available, comprehensive review designed to assist residents to work through common clinical scenarios encountered in CT training, clinical practice, and on the oral boards.

This spring, the TSRA will launch the new TSRA Operative Dictations in Cardiothoracic Surgery, a review of key operative indications and steps for a variety of adult cardiac, general thoracic, and congenital operations as well example templates to assist in operative dictations, and the TSRA Journal Club, an online resource that offers residents an easily accessible library of seminal and current journal articles in the areas of cardiac, thoracic, and congenital heart surgery.

The TSRA is an entirely resident run organization that strongly encourages the active participation of all CT surgical trainees. To learn more about our organization, visit our webpage (www.tsranet.org) and/or on visit us on Facebook (www.facebook.com/thoracicsurgeryresidentsassociation).

Bleeding wound

The US Food and Drug Administration (FDA) has approved marketing of an expandable, multi-sponge wound dressing to control bleeding from certain types of wounds inflicted in battle.

The dressing, called XSTAT, is for military use only. It is intended for use on gunshot or shrapnel wounds in areas where a tourniquet cannot be placed, such as the groin or armpit.

The dressing can be used for up to 4 hours, which could allow time for a patient to receive surgical care.

XSTAT consists of 3 syringe-style applicators containing 92 compressed cellulose sponges that have an absorbent coating.

The sponges expand and swell to fill the wound cavity, after approximately 20 seconds upon contact with water from blood or bodily fluid. This creates a temporary physical barrier to blood flow.

The number of sponges needed for effective hemorrhage control will vary depending on the size and depth of the wound. Up to 3 applicators may be used on a patient.

The tablet-shaped sponges are each 9.8 mm in diameter and 4 mm to 5 mm in height. They can absorb 3 mL of blood or body fluid. An applicator filled with 92 sponges, therefore, can absorb about 300 mL of fluid.

The sponges cannot be absorbed by the body, and all sponges must be removed before a wound is closed. For ease of visualization and to confirm removal of every sponge, each sponge contains a marker that is visible via X-ray.

The FDA reviewed XSTAT through its de novo classification process, a regulatory pathway for some novel, low-to-moderate-risk medical devices that are the first of their kind.

Before approving XSTAT, the FDA reviewed data from animal studies demonstrating the product’s ability to stop bleeding and its absorption capacity. The agency also reviewed non-clinical biocompatibility data and results of human factors testing.

XSTAT is manufactured by RevMedX, Inc., in Wilsonville, Oregon. For more information on XSTAT, see the company’s website.

Bleeding wound

The US Food and Drug Administration (FDA) has approved marketing of an expandable, multi-sponge wound dressing to control bleeding from certain types of wounds inflicted in battle.

The dressing, called XSTAT, is for military use only. It is intended for use on gunshot or shrapnel wounds in areas where a tourniquet cannot be placed, such as the groin or armpit.

The dressing can be used for up to 4 hours, which could allow time for a patient to receive surgical care.

XSTAT consists of 3 syringe-style applicators containing 92 compressed cellulose sponges that have an absorbent coating.

The sponges expand and swell to fill the wound cavity, after approximately 20 seconds upon contact with water from blood or bodily fluid. This creates a temporary physical barrier to blood flow.

The number of sponges needed for effective hemorrhage control will vary depending on the size and depth of the wound. Up to 3 applicators may be used on a patient.

The tablet-shaped sponges are each 9.8 mm in diameter and 4 mm to 5 mm in height. They can absorb 3 mL of blood or body fluid. An applicator filled with 92 sponges, therefore, can absorb about 300 mL of fluid.

The sponges cannot be absorbed by the body, and all sponges must be removed before a wound is closed. For ease of visualization and to confirm removal of every sponge, each sponge contains a marker that is visible via X-ray.

The FDA reviewed XSTAT through its de novo classification process, a regulatory pathway for some novel, low-to-moderate-risk medical devices that are the first of their kind.

Before approving XSTAT, the FDA reviewed data from animal studies demonstrating the product’s ability to stop bleeding and its absorption capacity. The agency also reviewed non-clinical biocompatibility data and results of human factors testing.

XSTAT is manufactured by RevMedX, Inc., in Wilsonville, Oregon. For more information on XSTAT, see the company’s website.

Bleeding wound

The US Food and Drug Administration (FDA) has approved marketing of an expandable, multi-sponge wound dressing to control bleeding from certain types of wounds inflicted in battle.

The dressing, called XSTAT, is for military use only. It is intended for use on gunshot or shrapnel wounds in areas where a tourniquet cannot be placed, such as the groin or armpit.

The dressing can be used for up to 4 hours, which could allow time for a patient to receive surgical care.

XSTAT consists of 3 syringe-style applicators containing 92 compressed cellulose sponges that have an absorbent coating.

The sponges expand and swell to fill the wound cavity, after approximately 20 seconds upon contact with water from blood or bodily fluid. This creates a temporary physical barrier to blood flow.

The number of sponges needed for effective hemorrhage control will vary depending on the size and depth of the wound. Up to 3 applicators may be used on a patient.

The tablet-shaped sponges are each 9.8 mm in diameter and 4 mm to 5 mm in height. They can absorb 3 mL of blood or body fluid. An applicator filled with 92 sponges, therefore, can absorb about 300 mL of fluid.

The sponges cannot be absorbed by the body, and all sponges must be removed before a wound is closed. For ease of visualization and to confirm removal of every sponge, each sponge contains a marker that is visible via X-ray.

The FDA reviewed XSTAT through its de novo classification process, a regulatory pathway for some novel, low-to-moderate-risk medical devices that are the first of their kind.

Before approving XSTAT, the FDA reviewed data from animal studies demonstrating the product’s ability to stop bleeding and its absorption capacity. The agency also reviewed non-clinical biocompatibility data and results of human factors testing.

XSTAT is manufactured by RevMedX, Inc., in Wilsonville, Oregon. For more information on XSTAT, see the company’s website.