Postdural puncture headache (PDPH) has been a known complication of neuraxial anesthesia since the first spinal anesthetic was performed in 1898 by Bier.1 Bier attempted a spinal anesthetic on his research assistant, Hildebrandt, but was not able to inject the local anesthetic, so his research assistant then placed the spinal in Bier. The spinal anesthetic worked, but Bier developed a severe positional headache that lasted 9 days during which time he was confined to bed. Hildebrandt developed a headache that lasted 4 days. PDPH is not only an issue for the anesthesiologist, because neurologists and internists may see patients with PDPH after lumbar puncture or even spontaneous or traumatic cerebrospinal fluid leak. When PDPH complicates neuraxial analgesia for labor and delivery, it can be particularly distressing for both the obstetric anesthesiologist and the patient alike. Increased length of stay and cost of care and decreased patient satisfaction can all result from PDPH.2
Treatment options for PDPH vary greatly. Many institutions have no guidelines or protocols for prophylaxis or treatment, which makes the management of PDPH quite heterogeneous.3 Although few would argue that epidural blood patch (EBP) is the definitive treatment, there is considerable debate on which patients are candidates, how soon after dural puncture EBP can be performed, and how to manage the patient in whom initial EBP fails. In addition, a subset of patients will either refuse the EBP or not be considered candidates because of a variety of factors including but not limited to postpartum coagulopathy, fever, or preeclampsia. Those with preeclampsia, even without a coagulopathy, have altered cerebral perfusion,4–6 which could be worsened by injecting blood into the neuraxis. The purpose of this article is to review the efficacy of non-EBP treatment modalities for the treatment of PDPH (Table).
Initial treatment regimens center on noninvasive modalities to counteract the proposed mechanisms of PDPH; cerebrospinal fluid (CSF) loss and cerebral vasodilation. For example, hydration therapy has been proposed to increase CSF production.7 Although this modality has remained popular, to date, there is no evidence to support its use.8
In addition to hydration therapy, other conservative options include bed rest,9 supine/prone positioning,10–12 and abdominal binders.13,14 Bed rest comes with its own potential complications including but not limited to thromboembolic disease such as deep venous thrombosis, which may include cerebral vein thrombosis. Bed rest may be necessary in the short term if symptoms are severe; however, bed rest only alleviates the pain while in the supine position but does not treat the headache—when the patient sits up, the headache recurs.8 Prone positioning increases intra-abdominal pressure raising epidural space pressure and may provide symptomatic relief.12 Abdominal binders work via the same mechanism and may alleviate the headache.14 To be effective, they must be tightly applied and can be very uncomfortable for patients. There are currently no data to support the claim that abdominal binders shorten the duration of PDPH; however, one small study of women receiving spinal anesthesia with a 22-gauge needle for cesarean delivery was able to demonstrate a decrease in incidence of the headache when the binder was applied immediately after the procedure.13
Although there are no practice guidelines that recommend when EBP is indicated, untreated PDPH has been associated with rare complications such as cortical venous thrombosis15 and subdural hematoma.16 As such, those with severe headaches or those who have not responded to conservative therapy in a timely manner may benefit from invasive treatments such as EBP. Severe symptoms or focal neurologic findings indicate imaging to exclude serious intracranial pathology before attempting EBP or conservative therapy.
A host of medications have been trialed in the hope of finding an effective noninvasive treatment for PDPH. Reviewing every medication or formulation goes beyond the scope of this brief review. Therefore, a concise review of the more commonly used medications will be provided.
Nonsteroidal Anti-inflammatory Drugs, Acetaminophen, Barbiturates, and Combinations.
First-line medications that are often trialed in patients where a conservative pathway is attempted are nonsteroidal anti-inflammatory drugs, acetaminophen, opioids such as oxycodone, or combination medications commonly prescribed for tension and migraine headaches, where barbiturates (butalbital), acetaminophen, and caffeine (discussed below) are added in a single formulation. Data on the efficacy of these medications are lacking, although they are often mentioned in conservative treatment pathways and are often used in control arms of other studies.17–19 A survey of practitioner management regimens for PDPH performed by Baysinger et al20 reported that medications such as nonsteroidal anti-inflammatory drugs and opioids were employed by 87% and 71% of respondents, respectively. The reported success rates to these treatments, however, were low, with over 60% of respondents reporting that these medications were successful less than 40% of the time, and 34% of respondents reporting a success rate of less than 20%.
Methylxanthines, namely caffeine and theophylline, are some of the most studied medications for relief of PDPH. These medications treat PDPH symptomatology by 2 mechanisms. First, these drugs interfere with calcium uptake by the sarcoplasmic reticulum, block phosphodiesterase, and antagonize adenosine, which all result in cerebral vasoconstriction.21,22 Second, methylxanthines increase CSF production by stimulating sodium-potassium pumps.23
The data on caffeine are highly heterogeneous as both intravenous (IV) and oral formulations at varying dosages and intervals were utilized during the investigations. Most studies also had small sample sizes and different end points, which further limits conclusions. Caffeine-dosing regimens are usually in the 300- to 500-mg range administered orally or intravenously twice per day.14 For comparison, a standard cup of coffee has between 50 and 100 mg caffeine.14 The oral bioavailability of caffeine approaches 100% with little first-pass metabolism, so either route of administration is acceptable.24
Camann et al25 enrolled 40 postpartum women and randomly assigned them to either 300 mg oral caffeine versus placebo and analyzed change in visual analogue scale (VAS) at 4 and 24 hours along with the need for EBP. At 4 hours, VAS scores in the caffeine group were lower (33 ± 6) than the placebo group (49 ± 7); however, this difference was ablated by 24 hours. The need for EBP trended in favor of caffeine use (7/20 in caffeine group versus 11/20 in placebo group; relative risk [RR], 0.64; confidence interval [CI], 0.31–1.3) but did not meet statistical significance. Sechzer26 randomly assigned 41 patients to receive either IV caffeine or placebo and recorded persistence of headache at 1 and 2 hours after intervention. He found an RR of 0.29 (0.13–0.64) for persistent headache for those in the caffeine group supporting its use. Caffeine is not recommended in women with hypertension or seizure disorder27 because therapeutic levels of caffeine have been associated with central nervous system (CNS) toxicity and atrial fibrillation.14,27 Also, 1 investigator reported seizures after caffeine administration in a postpartum patient after a 500-mg IV infusion.28 Caffeine is excreted into breast milk with milk to plasma ratios of 0.5 to 0.76.29,30 Amounts of caffeine excreted into breast milk are not likely to be clinically relevant, although reports of infant sleep disturbance with very heavy maternal caffeine use (10–20 cups per day) have been reported.31
Theophylline has been used to treat PDPH, with both oral (281.7 mg 3× per day)17 and intravenous regimens (200 mg infused over 30 minutes once).32 Although the mechanism of action is similar to caffeine, theophylline tends to be used less than caffeine.7 This is likely because of both the narrow therapeutic index with theophylline and the patient experience with caffeine. Mahoori et al18 conducted a study in 60 patients (31.6% female) who were randomly assigned to receive either 250 mg theophylline or 500 mg acetaminophen orally every 8 hours and evaluated VAS scores for pain at 2, 6, and 12 hours after the initial dose. They found mean differences in VAS scores of −0.97 (CI, −1.69 to −0.25), −0.9 (CI, −1.72 to −0.08), and −1.57 (CI, −2.67 to −0.47) at 2, 6, and 12 hours, respectively. Other studies have found similar results, although they were smaller studies.17,23,32,33 Less than 1% of the maternal dose of theophylline is excreted into breast milk.34 It has been associated with irritability in young infants where mothers took a rapidly absorbing formulation of a similar drug aminophylline.35 It is considered to be compatible with breast-feeding by the American Academy of Pediatrics.36
Although the evidence for methylxanthines is limited, it remains a popular treatment choice given its reported efficacy, favorable side effect profile, and ease of use. The authors of this article commonly suggest to their patients to drink caffeinated coffee, which is generally well received by the patient while deciding if they want an EBP or in those who are not candidates. Our approach is in agreement with a Cochrane review on the topic.37
Medications, adreno-corticotropic hormone (ACTH) and hydrocortisone, that interact with the adrenocorticotropic hormonal axis have also been proposed as a therapeutic option. The mechanism of action by which these medications treat PDPH is unclear, but several theories exist including expansion of blood volume by releasing aldosterone,38 dural edema causing overlap of dural hole,39 increasing CSF production through sodium active transport,40 or increasing brain β-endorphins (see Figure 1).41
Natural ACTH is a 39-amino-acid protein in which the first 24 amino acids in the sequence provide its hormonal activity.42 The remaining 15 amino acids are nonactive and antigenic. Synthetic ACTH (cosyntropin) is an analog of only the first 24 amino acids in the chain, giving it hormonal efficacy with less antigenicity.42 Synthetic ACTH infusions of 0.25 to 0.75 mg over 4 to 8 hours have mostly been described in small case series,40,41,43,44 which limits definitive conclusions. In 2004, Rucklidge et al45 randomly assigned 18 female patients to intramuscular formulations of synthetic ACTH or saline injections and tracked request for EBP, as well as VAS pain scores. No significant differences were seen. Zeger et al46 randomly assigned 33 patients with PDPH (60% female) to either cosyntropin or caffeine and examined VAS scores and persistence of headache. Both groups showed a decrease in VAS score, 80% in the cosyntropin group versus 56% in the caffeine group 2 hours after treatment, although there was no difference in the need for supplemental analgesics between groups. Hakim38 administered 1 mg cosyntropin 30 minutes postdelivery in 90 patients (45 intervention versus 45 control) who experienced accidental dural puncture (ADP) and found that less patients developed PDPH (33.3% vs 68.9%; P = .001). Of the patients that did develop headaches, fewer required EBP (11.1% vs 28.9%; P = .035). The use of ACTH seems promising; however, a Cochrane review on the topic37 does not recommend its use and the authors of this article agree because the evidence is conflicting. No reports examining the use of synthetic ACTH have been published, and its use in breast-feeding “probably is compatible.”47
Both Noyan Ashraf et al19 and Alam et al48 examined the effectiveness of a course of hydrocortisone, one of the end hormones in the hypophyseal-pituitary-adrenal axis, for PDPH. In each study, the participants received a bolus (200 mg19 or 100 mg48 IV) followed by repeat 100-mg dosing every 8 hours for 48 hours. VAS scores and the need for EBP were examined. Statistically significant decreases in VAS scores were found at 6, 24, and 48 hours in the hydrocortisone group in both studies when compared with the control arm. However, no difference in the need for EBP was found in either study. Two other randomized controlled trials (RCTs) did not demonstrate a benefit of corticosteroids, and the authors of this article do not routinely use them for the prevention or treatment of PDPH.49,50 A Cochrane review37 examining the potential use of hydrocortisone reports efficacy in pain score reduction; however, the authors believe better alternatives exist, such as caffeine, that are more efficacious and have been more extensively studied. There are currently no data reporting the transfer of exogenous hydrocortisone into breast milk; however, it is unlikely that it would pose a risk, because prednisone, a much more potent corticosteroid is compatible with breast-feeding.36
Medications Effective for Headache and Neuropathic Pain.
Pharmacologic therapy with medications effective in treating other headache and pain syndromes has also been trialed. Sumatriptan, a serotonin type 1-d receptor agonist, commonly used in treating migraines, showed promise in early case series studies.51 However, to date, RCTs examining its efficacy have yielded negative results,52,53 a finding that is concordant with the conclusions from the Cochrane review.37 Sumatriptan is excreted into human breast milk in negligible quantities and is no longer expressed 8 hours after a dose.54 It is classified as compatible with breast-feeding.36 Methylergonovine, a commonly used uterotonic agent, has also been used to treat migraines because of its alpha activity.55 Hakim et al56 performed the largest case series examining methergine for the treatment of PDPH. In this series, 25 obstetric patients who developed PDPH after spinal anesthesia in whom conservative therapy for 24 hours failed were given oral methergine 0.25 mg 3 times per day for 24 hours. If symptoms were reduced or resolved, the treatment was continued for 48 additional hours. VAS scores were tracked every 8 hours on a 1 to 10 scale. Every patient except for one had improvement of symptoms with 16% experiencing total resolution, and pain scores were reduced by half the original value in 80% of patients. By day 3, 24 patients had resolution of the headache. One patient required EBP. Although these results are impressive, RCTs should be performed before drawing definitive conclusions and before prescribing methylergonovine to treat PDPH outside the context of a clinical trial. This is in contrast with the Cochrane review that reports efficacy based on the aforementioned results.37 Methylergonovine is excreted into breast milk in very small amounts that are not clinically relevant.57 There is some debate on the effect of methylergonovine with regard to its effect on prolactin. Structurally similar to bromocriptine, which is known to inhibit prolactin, methylergonovine has been implicated in decreasing prolactin levels in the immediate postpartum period.58 A case-control study of 20 women demonstrated a drop in prolactin levels that was significant when mothers were treated for 7 days; however, milk let down, milk volume, and infant weight gain were the same between those treated and controls.59 It is considered to be compatible with breast-feeding.36
Gabapentin, a synthetic analogue of γ-aminobutyric acid, has also been investigated as a possible therapy.60–63 It has analgesic properties and can inhibit the sympathetic pathway of pain,64 which may contribute to the pain of PDPH.62 Gabapentin selectively inhibits alpha-2-delta presynaptic voltage-gated channels that decreases calcium influx inhibiting excitatory neurotransmitters from primary afferent nerves. At the level of the spinal cord, gabapentin modulates presynaptic N-methyl-d-aspartate receptors.65
A case series by Wagner et al62 examined 17 patients in whom EBP was contraindicated, refused by the patient, or was ineffective in treating the headache. All patients were given a 200-mg per os (PO) load dose of gabapentin followed by 100- to 300-mg maintenance doses 3 times daily (TID) titrated to side effects. The most common reason for decreasing dose was sedation. They found that 9 patients (53%) had a decrease in VAS score of at least 2 of 10 points, as well as the resumption of normal activities within 24 to 48 hours of therapy initiation. It was found to be ineffective in 5 patients (29%). In 2006, Erol61 randomly assigned 20 patients to either 300 mg gabapentin PO TID or placebo and examined an 11-point VAS score over 4 days. Statistically significant reductions in scores were noted in the gabapentin group on each day with mean differences of −1.6 (CI, −1.92 to −1.28), −2.6 (CI, −2.87 to −2.33), −2.9 (CI, −3.1 to −2.7), and −1.6 (CI, −1.74 to −1.46), respectively. Erol60 randomly assigned 42 patients (40% female) to either 300 mg gabapentin PO TID or ergotamine and caffeine TID for 4 days. These investigators found significant reductions in pain scores on day 2 (mean difference [MD] −1.86; CI, −2.57 to −0.15) and day 3 (MD −2.38; CI, −2.94 to −1.82) but not on day 1 or 4 of treatment with gabapentin. We recommend gabapentin as a potential therapeutic option, in line with the Cochrane review on the topic.37 It should be noted that gabapentin crosses into breast milk at 12% of maternal levels,66 which has led some investigators to exclude lactating women from enrollment.62
Pregabalin, a medication with structural and mechanistic similarities to gabapentin, has also been trialed.65,67,68 Compared with gabapentin, pregabalin has a higher affinity for alpha-2-delta receptors, and analgesic efficacy corresponds to its affinity.69 Pregabalin also has greater oral bioavailability, has a faster time to peak concentration, and has a much shorter titration period.69,70 Huseyinoglu et al67 randomly assigned 40 patients with PDPH to a pregabalin regimen (150 mg/d for 3 days followed by 300 mg/d for 2 days) or placebo. VAS pain scores were significantly lower in the treatment group on days 2 to 5, and the treatment group required less diclofenac breakthrough as well. Mahoori et al71 randomly assigned 90 PDPH patients to pregabalin, gabapentin, or acetaminophen and found significant reduction in pain scores in both the gabapentin and the pregabalin group compared with acetaminophen at 24, 48, and 72 hours. These reductions were more pronounced in the pregabalin group, which led these investigators to conclude that pregabalin is a more effective treatment than gabapentin. More research is needed about pregabalin, but we expect it will ultimately prove efficacious based on its similar mechanism of action to gabapentin. The Cochrane review also concluded that, at this time, there are insufficient data to recommend its use.37 Lactation studies with pregabalin are small; however, recent data suggest that 0.2% of a 300-mg dose will pass into breast milk, which is 0.31 mg/kg/d in the infant.72 The significance of this dose is unknown.
Occasionally, patients need or opt for invasive treatments, but refuse or cannot safely receive EBP. When the use of blood is refused or contraindicated, but access to the epidural space is not, neuraxial injections of fluids or drugs may be considered. More commonly, patients refuse or are not candidates for epidural injection, but request additional therapy beyond oral or parenteral medications. In these cases, regional anesthetics (eg, occipital nerve block, sphenopalatine ganglion [SPG] nerve block) or alternative treatments (eg, acupuncture) may be offered.
Epidural Injections of Fluid
Non–blood-containing epidural injections have been trialed to treat or prevent PDPH. Epidural saline has been attempted for both prophylaxis and treatment of PDPH.73–77 Most studies have found saline to be less effective than EBP and of transient benefit because the saline resorbs from the epidural space. Bart and Wheeler78 randomly assigned 43 patients to either epidural injection of saline or blood. The investigators found that, although both groups had nearly 100% relief of symptoms postinjection, at 24-hour follow-up, up to 40% of those with 25-gauge dural punctures and 100% of those with 17-gauge dural punctures had recurrence of the headache. In the EBP group, 100% of patients with a 25-gauge dural puncture and 73% of patients with 17-gauge dural puncture experienced relief of symptoms at 24 hours.
Epidural hydroxyethyl starch has also been attempted.79,80 Documented case series show limited effectiveness and the need for multiple epidural injections to sustain the effect. There are currently no trials comparing hydroxyethyl starch with other treatment modalities including EBP. In an attempt to mimic the sealing effect of an EBP, fibrin glue derived from pooled plasma proteins has also been trialed81,82 with some efficacy; however, the data are only from very small case series, the procedure is invasive, and long-term sequelae are unclear.
Epidural Injections of Medications
Given the effectiveness of parental steroids in certain studies,49,50 epidural injections of dexamethasone have also been attempted. Najafi et al83 randomly assigned over 200 patients to either spinal anesthesia alone or spinal anesthesia followed immediately by epidural injection of 8 mg dexamethasone. No decrease in either the incidence or the severity of PDPH was seen.
Injections of epidural morphine were studied by 2 investigators. Cesur et al84 randomly assigned 52 parturients who experienced ADP during epidural catheter placement for cesarean delivery to either repeat epidural placement followed by epidural postoperative pain control or a control group who received either spinal or general anesthesia for the cesarean delivery followed by intramuscular meperidine and tramadol for postoperative pain control. In the epidural group, patients with a general (nonheadache) pain score greater than VAS 3 were given 3 mg epidural morphine. The investigators found reductions in the incidence of PDPH (7.1% vs 58%; P = .000), as well as decreased need for EBP (3.6% vs 37.5%; P = .002) in the morphine group. In another study performed in laboring patients by Al-Metwalli,85 the effect of epidural morphine was examined. Patients who experienced ADP had the repeat epidural catheter left in situ. After resolution of the anesthetic, 3 mg morphine was administered through the catheter, which was then left in situ for 24 hours. At the end of 24 hours, another dose of 3 mg epidural morphine was administered. The control group received 2 epidural saline boluses. Of the 25 patients in the morphine arm, only 12% developed a PDPH, none of whom required EBP compared with 12 patients who developed PDPH in the saline arm where 6 required EBP (P < .05). Although the focus of this article is on treatment modalities, in this study morphine was used in both a prophylactic and a therapeutic manner, and there are no studies examining the effect of epidural morphine in a purely therapeutic setting. The authors of this article believe that epidural morphine is promising, safe, and should be considered as a potential modality for both prophylaxis and treatment of PDPH. A limiting factor for its routine use might be the requirement for postadministration respiratory monitoring for 24 hours, which may preclude its use in outpatients or patients pending discharge. In addition, to follow the protocol described by Al-Metwalli,85 the epidural catheter would have to be left in situ for 24 hours unless a new epidural injection could feasibly be performed.
Small case series have demonstrated effectiveness in using acupuncture to treat PDPH.86–88 Acupuncture is known to have a suppressive effect on the trigeminal nucleus caudalis (TNC),89 which may play a role in PDPH. Acupuncture may also suppress nociception at the dorsal horn at the medulla spinal level90 and may have an overall inhibitory effect on the pain process.91 It should be noted that, in addition to traditional acupuncture sites such as BL 2, 10, 60, 62, GB 20, L I4, LR 3, and SI 3 (head, hand, and foot), those opting for auricular acupuncture sites were treated at MA-TF1, MA-AH9, and MA-AT1 bilaterally (see Figure 2). Dietzel et al92 described a series of 5 patients with PDPH who received acupuncture in lieu of EBP. After the treatments, all patients exhibited at least a 50% reduction in symptomatology, with no patients requiring EBP.
Sharma and Cheam87 and Volkan Acar et al88 each presented 2 patients who were treated with acupuncture, and in all 4 patients, an EBP was not required. Further study is required to better determine its utility.
Occipital Nerve Blocks
Greater and lesser occipital nerve blocks have been utilized to treat cluster and migraine headaches, as well as occipital neuralgia.93,94 The greater occipital nerve is formed by sensory fibers that originate at C2-C3 vertebrae, which penetrate the semispinalis capitis and trapezius muscles on their route to the cranium.95–97 The sensory distribution extends over the posterior aspect of the head traveling anteriorly to the vertex abutting the area supplied by the ophthalmic division of the trigeminal nerve.97,98 Local anesthetic injection of the nerve by landmark (lateral to the nuchal midline and medial to the occipital artery99) or ultrasound guidance96,99 (see Figure 3) blocks sensation to the skin, muscles, and vasculature along the nerve distribution.100 In addition to the somatic innervation, the TNC lies in close proximity to the upper cervical nerve roots, and there appears to be an overlap of sensory input between these structures.101 Dural stretching may activate the TNC causing some of the pain from PDPH, and this pathway may be blocked by greater occipital nerve block (GONB).98,101
Data on the use of GONB for the treatment of PDPH are sparse. A 3-patient case series97 with favorable results has given rise to larger series and a small RCT. Niraj et al101 recruited 24 patients in 19 of whom conservative treatment had failed; 18 of 19 received GONB. In 12 patients (66%), complete relief of headache was observed, whereas 6 patients (33%) experienced partial relief and requested EBP. Akyol et al99 retrospectively reviewed 21 patients with VAS scores greater than 4 who were offered GONB as part of a PDPH protocol. In this study, the investigators demonstrated that in mild cases (VAS 4–6) they were able to achieve 100% recovery by the 24th hour after GONB. Patients with severe PDPH with a VAS of 7 to 9 were more likely to have recurrence of symptoms, although all patients in this study reported significant relief of symptoms. Naja et al102 randomly assigned 50 patients with PDPH to either nerve stimulator-guided greater and lesser occipital nerve blocks versus conservative therapy. The investigators found complete relief in 68.4% of patients after 1 to 2 blocks, with an additional 31.6% requiring 4 blocks for total relief. Potential complications of GONB include bleeding, infection, and intravascular injection.99 These complications can be minimized through the use of proper sterile technique and the use of ultrasound guidance. Other side effects may depend on the injectate. Injections that contain steroids may cause alopecia and skin atrophy at the site if repeated injections are used.103
SPG Nerve Blocks
The SPG is an extracranial structure located within the pterygopalatine fossa that contains sympathetic, parasympathetic, and somatic sensory nerve fibers.104 It can be accessed via the transnasal or transcutaneous approach, although only the transnasal approach, using long cotton-tip applicators, has been described in treating PDPH104–107 (see Figure 4). This method is believed to work by blocking parasympathetic outflow to cerebral vasculature, which halts vasodilation.108 Although different local anesthetics and concentrations have been utilized, the largest case series presented by Cohen et al106,107 demonstrated success with both 4% lidocaine solution and 5% lidocaine ointment. In each case, the applicators were placed one per nostril and left in place for at least 10 minutes. The success rate was high with 69% of patients not requiring EBP after treatment.106 Further study is required to better determine its utility.
PDPH continues to be a major source of morbidity and dissatisfaction for parturients. Although the standard definitive treatment is EBP, many patients are either not candidates or refuse the invasive procedure. Multiple pharmacologic interventions have been trialed with mixed results, and any conclusions drawn are limited by small patient populations and study heterogeneity. All IV and oral analgesics have some utility but are generally limited by their duration of action. Non–blood-containing epidural injections (saline, hetastarch, fibrin glue) are of limited value because they are invasive, and if an epidural technique is being performed, injecting blood, which is known to work, is a better choice. Data on epidural morphine are favorable and because of its long duration of action may obviate the need for EBP. Finally, alternatives such as acupuncture and regional anesthesia (GONB and SPG blockade) show promise, but clinical use is still in its infancy.
Name: Daniel Katz, MD.
Contribution: This author was the original contributor and author.
Name: Yaakov Beilin, MD.
Contribution: This author was the original contributor and author.
This manuscript was handled by: Jill M. Mhyre, MD.
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